Rader DJ

References (62)

Title : Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial - Rosenson_2023_Nat.Med__
Author(s) : Rosenson RS , Gaudet D , Ballantyne CM , Baum SJ , Bergeron J , Kershaw EE , Moriarty PM , Rubba P , Whitcomb DC , Banerjee P , Gewitz A , Gonzaga-Jauregui C , McGinniss J , Ponda MP , Pordy R , Zhao J , Rader DJ
Ref : Nat Med , : , 2023
Abstract : Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg(-1) or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 .
ESTHER : Rosenson_2023_Nat.Med__
PubMedSearch : Rosenson_2023_Nat.Med__
PubMedID: 36879129
Gene_locus related to this paper: human-LPL

Title : Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins - Khetarpal_2021_PLoS.Genet_17_e1009802
Author(s) : Khetarpal SA , Vitali C , Levin MG , Klarin D , Park J , Pampana A , Millar JS , Kuwano T , Sugasini D , Subbaiah PV , Billheimer JT , Natarajan P , Rader DJ
Ref : PLoS Genet , 17 :e1009802 , 2021
Abstract : Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.
ESTHER : Khetarpal_2021_PLoS.Genet_17_e1009802
PubMedSearch : Khetarpal_2021_PLoS.Genet_17_e1009802
PubMedID: 34543263
Gene_locus related to this paper: mouse-Lipg , human-LIPG

Title : LDL-Cholesterol Reduction by ANGPTL3 Inhibition in Mice Is Dependent on Endothelial Lipase -
Author(s) : Wu L , Soundarapandian MM , Castoreno AB , Millar JS , Rader DJ
Ref : Circulation Research , 127 :1112 , 2020
PubMedID: 32808882

Title : CRISPR\/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report - Zhang_2017_Arterioscler.Thromb.Vasc.Biol_37_2156
Author(s) : Zhang H , Shi J , Hachet MA , Xue C , Bauer RC , Jiang H , Li W , Tohyama J , Millar J , Billheimer J , Phillips MC , Razani B , Rader DJ , Reilly MP
Ref : Arterioscler Thromb Vasc Biol , 37 :2156 , 2017
Abstract : OBJECTIVE: To gain mechanistic insights into the role of LIPA (lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages. APPROACH AND RESULTS: We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) technology to knock out LIPA in human induced pluripotent stem cells and then differentiate to macrophage (human-induced pluripotent stem cells-derived macrophage [IPSDM]) to explore the human macrophage LIPA loss-of-function phenotypes. LIPA was abundantly expressed in monocyte-derived macrophages and was markedly induced on IPSDM differentiation to comparable levels as in human monocyte-derived macrophage. IPSDM with knockout of LIPA (LIPA(-/-)) had barely detectable LAL enzymatic activity. Control and LIPA(-/-) IPSDM were loaded with [(3)H]-cholesteryl oleate-labeled AcLDL (acetylated low-density lipoprotein) followed by efflux to apolipoprotein A-I. Efflux of liberated [(3)H]-cholesterol to apolipoprotein A-I was abolished in LIPA(-/-) IPSDM, indicating deficiency in LAL-mediated lysosomal cholesteryl ester hydrolysis. In cells loaded with [(3)H]-cholesterol-labeled AcLDL, [(3)H]-cholesterol efflux was, however, not different between control and LIPA(-/-) IPSDM. ABCA1 (ATP-binding cassette, subfamily A, member 1) expression was upregulated by AcLDL loading but to a similar extent between control and LIPA(-/-) IPSDM. In nonlipid loaded state, LIPA(-/-) IPSDM had high levels of cholesteryl ester mass compared with minute amounts in control IPSDM. Yet, with AcLDL loading, overall cholesteryl ester mass was increased to similar levels in both control and LIPA(-/-) IPSDM. LIPA(-/-) did not impact lysosomal apolipoprotein-B degradation or expression of IL1B, IL6, and CCL5. CONCLUSIONS: LIPA(-/-) IPSDM reveals macrophage-specific hallmarks of LIPA deficiency. CRISPR/Cas9 and IPSDM provide important tools to study human macrophage biology and more broadly for future studies of disease-associated LIPA genetic variation in human macrophages.
ESTHER : Zhang_2017_Arterioscler.Thromb.Vasc.Biol_37_2156
PubMedSearch : Zhang_2017_Arterioscler.Thromb.Vasc.Biol_37_2156
PubMedID: 28882870

Title : Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease - Khera_2017_JAMA_317_937
Author(s) : Khera AV , Won HH , Peloso GM , O'Dushlaine C , Liu D , Stitziel NO , Natarajan P , Nomura A , Emdin CA , Gupta N , Borecki IB , Asselta R , Duga S , Merlini PA , Correa A , Kessler T , Wilson JG , Bown MJ , Hall AS , Braund PS , Carey DJ , Murray MF , Kirchner HL , Leader JB , Lavage DR , Manus JN , Hartzel DN , Samani NJ , Schunkert H , Marrugat J , Elosua R , McPherson R , Farrall M , Watkins H , Lander ES , Rader DJ , Danesh J , Ardissino D , Gabriel S , Willer C , Abecasis GR , Saleheen D , Dewey FE , Kathiresan S
Ref : Jama , 317 :937 , 2017
Abstract : Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305699 individuals of the Global Lipids Genetics Consortium and up to 120600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32646 control participants (0.32%) and 83 of 14245 participants with early-onset CAD (0.58%). Compared with 46703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 x 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
ESTHER : Khera_2017_JAMA_317_937
PubMedSearch : Khera_2017_JAMA_317_937
PubMedID: 28267856
Gene_locus related to this paper: human-LPL

Title : Lysosomal Acid Lipase Deficiency--A New Therapy for a Genetic Lipid Disease -
Author(s) : Rader DJ
Ref : N Engl J Med , 373 :1071 , 2015
PubMedID: 26352819

Title : Role of SN1 lipases on plasma lipids in metabolic syndrome and obesity - Miksztowicz_2014_Arterioscler.Thromb.Vasc.Biol_34_669
Author(s) : Miksztowicz V , Schreier L , McCoy M , Lucero D , Fassio E , Billheimer J , Rader DJ , Berg G
Ref : Arterioscler Thromb Vasc Biol , 34 :669 , 2014
Abstract : OBJECTIVE: To assess the phospholipase activity of endothelial (EL) and hepatic lipase (HL) in postheparin plasma of subjects with metabolic syndrome (MS)/obesity and their relationship with atherogenic and antiatherogenic lipoproteins. Additionally, to evaluate lipoprotein lipase (LPL) and HL activity as triglyceride (TG)-hydrolyses to complete the analyses of SN1 lipolytic enzymes in the same patient. APPROACH AND
RESULTS: Plasma EL, HL, and LPL activities were evaluated in 59 patients with MS and 36 controls. A trend toward higher EL activity was observed in MS. EL activity was increased in obese compared with normal weight group (P=0.009) and was negatively associated with high-density lipoprotein-cholesterol (P=0.014 and P=0.005) and apolipoprotein A-I (P=0.045 and P=0.001) in control and MS group, respectively. HL activity, as TG-hydrolase, was increased in MS (P=0.025) as well as in obese group (P=0.017); directly correlated with low-density lipoprotein-cholesterol (P=0.005) and apolipoprotein B (P=0.003) and negatively with high-density lipoprotein-cholesterol (P=0.021) in control group. LPL was decreased in MS (P<0.001) as well as in overweight and obese compared with normal weight group (P=0.015 and P=0.004, respectively); inversely correlated %TG-very low-density lipoproteins (P=0.04) and TG/apolipoprotein B index (P=0.013) in control group. These associations were not found in MS.
CONCLUSIONS: We describe for the first time EL and HL activity as phospholipases in MS/obesity, being both responsible for high-density lipoprotein catabolism. Our results elucidate part of the remaining controversies about SN1 lipases activity in MS and different grades of obesity. The impact of insulin resistance on the activity of the 3 enzymes determines the lipoprotein alterations observed in these states.
ESTHER : Miksztowicz_2014_Arterioscler.Thromb.Vasc.Biol_34_669
PubMedSearch : Miksztowicz_2014_Arterioscler.Thromb.Vasc.Biol_34_669
PubMedID: 24458708
Gene_locus related to this paper: human-LIPC , human-LPL , human-LIPG

Title : Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species - Yang_2014_Lipids_49_505
Author(s) : Yang Y , Kuwano T , Lagor WR , Albert CJ , Brenton S , Rader DJ , Ford DA , Brown RJ
Ref : Lipids , 49 :505 , 2014
Abstract : Hepatic lipase (HL) and endothelial lipase (EL) share overlapping and complementary roles in lipoprotein metabolism. The deletion of HL and EL alleles in mice raises plasma total cholesterol and phospholipid concentrations. However, the influence of HL and EL in vivo on individual molecular species from each class of lipid is not known. We hypothesized that the loss of HL, EL, or both in vivo may affect select molecular species from each class of lipids. To test this hypothesis, we performed lipidomic analyses on plasma and livers from fasted female wild-type, HL-knockout, EL-knockout, and HL/EL-double knockout mice. Overall, the loss of HL, EL, or both resulted in minimal changes to hepatic lipids; however, select species of CE were surprisingly reduced in the livers of mice only lacking EL. The loss of HL, EL, or both reduced the plasma concentrations for select molecular species of triacylglycerol, diacylglycerol, and free fatty acid. On the other hand, the loss of HL, EL, or both raised the plasma concentrations for select molecular species of phosphatidylcholine, cholesteryl ester, diacylglycerol, sphingomyelin, ceramide, plasmanylcholine, and plasmenylcholine. The increased plasma concentration of select ether phospholipids was evident in the absence of EL, thus suggesting that EL might exhibit a phospholipase A2 activity. Using recombinant EL, we showed that it could hydrolyse the artificial phospholipase A2 substrate 4-nitro-3-(octanoyloxy)benzoic acid. In summary, our study shows for the first time the influence of HL and EL on individual molecular species of several classes of lipids in vivo using lipidomic methods.
ESTHER : Yang_2014_Lipids_49_505
PubMedSearch : Yang_2014_Lipids_49_505
PubMedID: 24777581
Gene_locus related to this paper: human-LIPC , human-LIPG

Title : Inhibition of endothelial lipase activity by sphingomyelin in the lipoproteins - Yang_2014_Lipids_49_987
Author(s) : Yang P , Belikova NA , Billheimer J , Rader DJ , Hill JS , Subbaiah PV
Ref : Lipids , 49 :987 , 2014
Abstract : Endothelial lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration-dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at the sn-2 position, generating the corresponding PUFA-lyso PtdCho. This specificity for PUFA-PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.
ESTHER : Yang_2014_Lipids_49_987
PubMedSearch : Yang_2014_Lipids_49_987
PubMedID: 25167836
Gene_locus related to this paper: human-LIPG

Title : Endothelial lipase is a critical determinant of high-density lipoprotein-stimulated sphingosine 1-phosphate-dependent signaling in vascular endothelium - Tatematsu_2013_Arterioscler.Thromb.Vasc.Biol_33_1788
Author(s) : Tatematsu S , Francis SA , Natarajan P , Rader DJ , Saghatelian A , Brown JD , Michel T , Plutzky J
Ref : Arterioscler Thromb Vasc Biol , 33 :1788 , 2013
Abstract : OBJECTIVE: In addition to an extensively characterized role of high-density lipoprotein (HDL) in reverse cholesterol transport, bioactive lipids bound to HDL can also exert diverse vascular effects. Despite this, integration of HDL action in the vasculature with pathways that metabolize HDL and release bioactive lipids has been much less explored. The effects of HDL on endothelial cells are mediated in part by HDL-associated sphingosine 1-phosphate (S1P), which binds to S1P1 receptors and promotes activation of endothelial NO synthase (eNOS) and the kinase Akt. In these studies, we characterized the role of endothelial lipase (EL) in the control of endothelial signaling and biology, including those mediated by HDL-associated S1P. APPROACH AND
RESULTS: HDL-induced angiogenesis in aortic rings from EL-deficient (EL(-/-)) mice was markedly decreased compared with wild-type controls. In cultured endothelial cells, small interfering RNA-mediated knockdown of EL abrogated HDL-promoted endothelial cell migration and tube formation. Small interfering RNA-mediated EL knockdown also attenuated HDL-induced phosphorylation of eNOS(1179) and Akt(473). S1P stimulation restored HDL-induced endothelial migration and Akt/eNOS phosphorylation that had been blocked by small interfering RNA-mediated EL knockdown. HDL-induced endothelial cell migration and Akt/eNOS phosphorylation were completely inhibited by the S1P1 antagonist W146 but not by the S1P3 antagonist CAY10444.
CONCLUSIONS: EL is a critical determinant of the effects of HDL on S1P-mediated vascular responses and acts on HDL to promote activation of S1P1, leading to Akt/eNOS phosphorylation and subsequent endothelial migration and angiogenesis. The role of EL in HDL-associated S1P effects provides new insights into EL action, the responses seen through EL and HDL interaction, and S1P signaling.
ESTHER : Tatematsu_2013_Arterioscler.Thromb.Vasc.Biol_33_1788
PubMedSearch : Tatematsu_2013_Arterioscler.Thromb.Vasc.Biol_33_1788
PubMedID: 23723371
Gene_locus related to this paper: human-LIPG

Title : Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia - Stitziel_2013_Arterioscler.Thromb.Vasc.Biol_33_2909
Author(s) : Stitziel NO , Fouchier SW , Sjouke B , Peloso GM , Moscoso AM , Auer PL , Goel A , Gigante B , Barnes TA , Melander O , Orho-Melander M , Duga S , Sivapalaratnam S , Nikpay M , Martinelli N , Girelli D , Jackson RD , Kooperberg C , Lange LA , Ardissino D , McPherson R , Farrall M , Watkins H , Reilly MP , Rader DJ , de Faire U , Schunkert H , Erdmann J , Samani NJ , Charnas L , Altshuler D , Gabriel S , Kastelein JJ , Defesche JC , Nederveen AJ , Kathiresan S , Hovingh GK
Ref : Arterioscler Thromb Vasc Biol , 33 :2909 , 2013
Abstract : OBJECTIVE: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family. APPROACH AND
RESULTS: We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance.
CONCLUSIONS: By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.
ESTHER : Stitziel_2013_Arterioscler.Thromb.Vasc.Biol_33_2909
PubMedSearch : Stitziel_2013_Arterioscler.Thromb.Vasc.Biol_33_2909
PubMedID: 24072694

Title : Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics - Larach_2013_Clin.Lipidol_8_635
Author(s) : Larach DB , Cuchel M , Rader DJ
Ref : Clin Lipidol , 8 :635 , 2013
Abstract : Identification of the CETP, LIPG (encoding endothelial lipase) and APOC3 genes, and ana lysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeutic efficacy. The case of endothelial lipase exemplifies the importance of utilizing population-wide genetic studies of rare variants in potential therapeutic targets to gain information on cardiovascular disease end points. Similar population-wide studies of cardiovascular end points make apoC-III a potentially attractive target for lipid-related drug discovery. These three cases illustrate the positives and negatives of single-gene studies relating to HDL-related cardiovascular drug discovery; such studies should focus not only on HDL cholesterol and other components of the lipid profile, but also on the effect genetic variants have on cardiovascular end points.
ESTHER : Larach_2013_Clin.Lipidol_8_635
PubMedSearch : Larach_2013_Clin.Lipidol_8_635
PubMedID: 25374625
Gene_locus related to this paper: human-LIPG

Title : Genetics of lipid traits and relationship to coronary artery disease - Keenan_2013_Curr.Cardiol.Rep_15_396
Author(s) : Keenan TE , Rader DJ
Ref : Curr Cardiol Rep , 15 :396 , 2013
Abstract : Despite the critical importance of plasma lipoproteins in the development of atherosclerosis, varying degrees of evidence surround the causal associations of lipoproteins with coronary artery disease (CAD). These causal contributions can be assessed by employing genetic variants as unbiased proxies for lipid levels. A relatively large number of low-density lipoprotein cholesterol (LDL-C) variants strongly associate with CAD, confirming the causal impact of this lipoprotein on atherosclerosis. Although not as firmly established, genetic evidence supporting a causal role of triglycerides (TG) in CAD is growing. Conversely, high-density lipoprotein cholesterol (HDL-C) variants not associated with LDL-C or TG have not yet been shown to be convincingly associated with CAD, raising questions about the causality of HDL-C in atherosclerosis. Finally, genetic variants at the LPA locus associated with lipoprotein(a) [Lp(a)] are decisively linked to CAD, indicating a causal role for Lp(a). Translational investigation of CAD-associated lipid variants may identify novel regulatory pathways with therapeutic potential to alter CAD risk.
ESTHER : Keenan_2013_Curr.Cardiol.Rep_15_396
PubMedSearch : Keenan_2013_Curr.Cardiol.Rep_15_396
PubMedID: 23881580

Title : Design and synthesis of boronic acid inhibitors of endothelial lipase - O'Connell_2012_Bioorg.Med.Chem.Lett_22_1397
Author(s) : O'Connell DP , LeBlanc DF , Cromley D , Billheimer J , Rader DJ , Bachovchin WW
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :1397 , 2012
Abstract : Endothelial lipase (EL) and lipoprotein lipase (LPL) are homologous lipases that act on plasma lipoproteins. EL is predominantly a phospholipase and appears to be a key regulator of plasma HDL-C. LPL is mainly a triglyceride lipase regulating (V)LDL levels. The existing biological data indicate that inhibitors selective for EL over LPL should have anti-atherogenic activity, mainly through increasing plasma HDL-C levels. We report here the synthesis of alkyl, aryl, or acyl-substituted phenylboronic acids that inhibit EL. Many of the inhibitors evaluated proved to be nearly equally potent against both EL and LPL, but several exhibited moderate to good selectivity for EL.
ESTHER : O'Connell_2012_Bioorg.Med.Chem.Lett_22_1397
PubMedSearch : O'Connell_2012_Bioorg.Med.Chem.Lett_22_1397
PubMedID: 22225633

Title : Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol - Khetarpal_2011_PLoS.Genet_7_e1002393
Author(s) : Khetarpal SA , Edmondson AC , Raghavan A , Neeli H , Jin W , Badellino KO , Demissie S , Manning AK , Derohannessian SL , Wolfe ML , Cupples LA , Li M , Kathiresan S , Rader DJ
Ref : PLoS Genet , 7 :e1002393 , 2011
Abstract : Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci.
ESTHER : Khetarpal_2011_PLoS.Genet_7_e1002393
PubMedSearch : Khetarpal_2011_PLoS.Genet_7_e1002393
PubMedID: 22174694
Gene_locus related to this paper: human-LIPG

Title : Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol - Edmondson_2011_Circ.Cardiovasc.Genet_4_145
Author(s) : Edmondson AC , Braund PS , Stylianou IM , Khera AV , Nelson CP , Wolfe ML , Derohannessian SL , Keating BJ , Qu L , He J , Tobin MD , Tomaszewski M , Baumert J , Klopp N , Doring A , Thorand B , Li M , Reilly MP , Koenig W , Samani NJ , Rader DJ
Ref : Circ Cardiovasc Genet , 4 :145 , 2011
Abstract : BACKGROUND: Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. METHODS AND
RESULTS: Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.
CONCLUSIONS: Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.
ESTHER : Edmondson_2011_Circ.Cardiovasc.Genet_4_145
PubMedSearch : Edmondson_2011_Circ.Cardiovasc.Genet_4_145
PubMedID: 21303902
Gene_locus related to this paper: human-LIPG

Title : Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function - Watson_2011_J.Lipid.Res_52_361
Author(s) : Watson CE , Weissbach N , Kjems L , Ayalasomayajula S , Zhang Y , Chang I , Navab M , Hama S , Hough G , Reddy ST , Soffer D , Rader DJ , Fogelman AM , Schecter A
Ref : J Lipid Res , 52 :361 , 2011
Abstract : L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.
ESTHER : Watson_2011_J.Lipid.Res_52_361
PubMedSearch : Watson_2011_J.Lipid.Res_52_361
PubMedID: 21068008

Title : VLDL hydrolysis by hepatic lipase regulates PPARdelta transcriptional responses - Brown_2011_PLoS.One_6_e21209
Author(s) : Brown JD , Oligino E , Rader DJ , Saghatelian A , Plutzky J
Ref : PLoS ONE , 6 :e21209 , 2011
Abstract : BACKGROUND: PPARs (alpha,gamma,delta) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown. METHODS/PRINCIPAL FINDINGS: Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL>>LDL, IDL) to activate PPARdelta preferentially over PPARalpha or PPARgamma, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARdelta in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARdelta target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPARdelta activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARdelta activation and ADRP gene regulation in vitro. CONCLUSIONS: These data define a novel pathway involving HL hydrolysis of VLDL that activates PPARdelta through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription.
ESTHER : Brown_2011_PLoS.One_6_e21209
PubMedSearch : Brown_2011_PLoS.One_6_e21209
PubMedID: 21750705

Title : A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease - Wild_2011_Circ.Cardiovasc.Genet_4_403
Author(s) : Wild PS , Zeller T , Schillert A , Szymczak S , Sinning CR , Deiseroth A , Schnabel RB , Lubos E , Keller T , Eleftheriadis MS , Bickel C , Rupprecht HJ , Wilde S , Rossmann H , Diemert P , Cupples LA , Perret C , Erdmann J , Stark K , Kleber ME , Epstein SE , Voight BF , Kuulasmaa K , Li M , Schafer AS , Klopp N , Braund PS , Sager HB , Demissie S , Proust C , Konig IR , Wichmann HE , Reinhard W , Hoffmann MM , Virtamo J , Burnett MS , Siscovick D , Wiklund PG , Qu L , El Mokthari NE , Thompson JR , Peters A , Smith AV , Yon E , Baumert J , Hengstenberg C , Marz W , Amouyel P , Devaney J , Schwartz SM , Saarela O , Mehta NN , Rubin D , Silander K , Hall AS , Ferrieres J , Harris TB , Melander O , Kee F , Hakonarson H , Schrezenmeir J , Gudnason V , Elosua R , Arveiler D , Evans A , Rader DJ , Illig T , Schreiber S , Bis JC , Altshuler D , Kavousi M , Witteman JC , Uitterlinden AG , Hofman A , Folsom AR , Barbalic M , Boerwinkle E , Kathiresan S , Reilly MP , O'Donnell CJ , Samani NJ , Schunkert H , Cambien F , Lackner KJ , Tiret L , Salomaa V , Munzel T , Ziegler A , Blankenberg S
Ref : Circ Cardiovasc Genet , 4 :403 , 2011
Abstract : BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7x10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3x10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4x10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
ESTHER : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedSearch : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedID: 21606135
Gene_locus related to this paper: human-LIPA

Title : Impact of combined deficiency of hepatic lipase and endothelial lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins - Brown_2010_Circ.Res_107_357
Author(s) : Brown RJ , Lagor WR , Sankaranaravanan S , Yasuda T , Quertermous T , Rothblat GH , Rader DJ
Ref : Circulation Research , 107 :357 , 2010
Abstract : RATIONALE: Hepatic lipase (HL) and endothelial lipase (EL) are extracellular lipases that both hydrolyze triglycerides and phospholipids and display potentially overlapping or complementary roles in lipoprotein metabolism. OBJECTIVE: We sought to dissect the overlapping roles of HL and EL by generating mice deficient in both HL and EL (HL/EL-dko) for comparison with single HL-knockout (ko) and EL-ko mice, as well as wild-type mice. METHODS AND RESULTS: Reproduction and viability of the HL/EL-dko mice were impaired compared with the single-knockout mice. The plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and phospholipids in the HL/EL-dko mice were markedly higher than those in the single-knockout mice. Most notably, the HL/EL-dko mice exhibited an unexpected substantial increase in small low-density lipoproteins. Kinetic studies with [(3)H]cholesteryl ether-labeled very-low-density lipoproteins demonstrated that the HL/EL-dko mice accumulated counts in the smallest low-density lipoprotein-sized fractions, as assessed by size exclusion chromatography, suggesting that it arises from lipolysis of very-low-density lipoproteins. HDL from all 3 lipase knockout models had an increased cholesterol efflux capacity but reduced clearance of HDL cholesteryl esters versus control mice. Despite their higher HDL cholesterol levels, neither HL-ko, EL-ko, nor HL/EL-dko mice demonstrated an increased rate of macrophage reverse cholesterol transport in vivo. CONCLUSIONS: These studies reveal an additive effect of HL and EL on HDL metabolism but not macrophage reverse cholesterol transport in mice and an unexpected redundant role of HL and EL in apolipoprotein B lipoprotein metabolism.
ESTHER : Brown_2010_Circ.Res_107_357
PubMedSearch : Brown_2010_Circ.Res_107_357
PubMedID: 20558822
Gene_locus related to this paper: human-LIPC , human-LIPG

Title : Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis - Yasuda_2010_Circ.J_74_2263
Author(s) : Yasuda T , Ishida T , Rader DJ
Ref : Circ J , 74 :2263 , 2010
Abstract : Endothelial lipase (EL) is a phospholipase that belongs to the lipoprotein lipase (LPL) family, which includes LPL and hepatic lipase (HL). Similar to LPL and HL, EL regulates lipoprotein metabolism, mainly high-density lipoprotein (HDL) metabolism and HDL cholesterol (HDL-C) levels in humans and mice. Existing data strongly suggest that inhibition of EL in humans would be expected to increase the HDL-C level. However, it has not been definitively established whether the effect of EL activity on HDL-C levels translates into effects on reverse cholesterol transport or atherosclerosis. The available data regarding the impact of EL expression and activity on HDL metabolism, reverse cholesterol transport, and atherosclerosis are reviewed.
ESTHER : Yasuda_2010_Circ.J_74_2263
PubMedSearch : Yasuda_2010_Circ.J_74_2263
PubMedID: 20962428

Title : Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases - Liu_2010_J.Biol.Chem_285_27561
Author(s) : Liu J , Afroza H , Rader DJ , Jin W
Ref : Journal of Biological Chemistry , 285 :27561 , 2010
Abstract : Lipoprotein lipase (LPL)-mediated lipolysis of triglycerides is the first and rate-limiting step in chylomicron/very low density lipoprotein clearance at the luminal surface of the capillaries. Angiopoietin-like protein 3 (ANGPTL3) is shown to inhibit LPL activity and plays important roles in modulating lipoprotein metabolism in vivo. However, the mechanism by which it inhibits LPL activity remains poorly understood. Using cell-based analysis of the interaction between ANGPTL3, furin, proprotein convertase subtilisin/kexin type 5 (PCSK5), paired amino acid converting enzyme-4 (PACE4), and LPL, we demonstrated that the cleavage of LPL by proprotein convertases is an inactivation process, similar to that seen for endothelial lipase cleavage. At physiological concentrations and in the presence of cells, ANGPTL3 is a potent inhibitor of LPL. This action is due to the fact that ANGPTL3 can enhance LPL cleavage by endogenous furin and PACE4 but not by PCSK5. This effect is specific to LPL but not endothelial lipase. Both N- and C-terminal domains of LPL are required for ANGPTL3-enhanced cleavage, and the N-terminal domain of ANGPTL3 is sufficient to exert its effect on LPL cleavage. Moreover, ANGPTL3 enhances LPL cleavage in the presence of either heparan sulfate proteoglycans or glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1). By enhancing LPL cleavage, ANGPTL3 dissociates LPL from the cell surface, inhibiting both the catalytic and noncatalytic functions of LPL. Taken together, our data provide a molecular connection between ANGPTL3, LPL, and proprotein convertases, which may represent a rapid signal communication among different metabolically active tissues to maintain energy homeostasis. These novel findings provide a new paradigm of specific protease-substrate interaction and further improve our knowledge of LPL biology.
ESTHER : Liu_2010_J.Biol.Chem_285_27561
PubMedSearch : Liu_2010_J.Biol.Chem_285_27561
PubMedID: 20581395

Title : Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans - Edmondson_2009_J.Clin.Invest_119_1042
Author(s) : Edmondson AC , Brown RJ , Kathiresan S , Cupples LA , Demissie S , Manning AK , Jensen MK , Rimm EB , Wang J , Rodrigues A , Bamba V , Khetarpal SA , Wolfe ML , Derohannessian S , Li M , Reilly MP , Aberle J , Evans D , Hegele RA , Rader DJ
Ref : J Clinical Investigation , 119 :1042 , 2009
Abstract : Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.
ESTHER : Edmondson_2009_J.Clin.Invest_119_1042
PubMedSearch : Edmondson_2009_J.Clin.Invest_119_1042
PubMedID: 19287092
Gene_locus related to this paper: human-LIPG

Title : The T111I variant in the endothelial lipase gene and risk of coronary heart disease in three independent populations - Jensen_2009_Eur.Heart.J_30_1584
Author(s) : Jensen MK , Rimm EB , Mukamal KJ , Edmondson AC , Rader DJ , Vogel U , Tjonneland A , Sorensen TI , Schmidt EB , Overvad K
Ref : Eur Heart J , 30 :1584 , 2009
Abstract : AIMS: Endothelial lipase (LIPG) is implicated in the metabolism of high-density lipoprotein cholesterol (HDL-C). Small studies in selected populations have reported higher HDL-C levels among carriers of the common T111I variant in LIPG, but whether this variant is associated with plasma lipids and risk of coronary heart disease (CHD) in the general population is unclear. The objective of this study was to address the associations of the T111I variant with plasma lipids and risk of CHD in three independent prospective studies of generally healthy men and women. METHODS AND RESULTS: The T111I variant was genotyped in case-control studies of CHD nested within the Diet, Cancer, and Health study with 998 cases, Nurses' Health Study with 241 cases, and Health Professionals Follow-up Study with 262 cases. The minor allele frequency in the combined pool of controls was 0.29. The T111I variant was not associated with HDL-C or any other lipid and lipoprotein measures. Compared with wildtype homozygotes, the pooled estimate for risk of CHD was 0.95 (0.85-1.06) per T111I allele. CONCLUSION: Our analysis among healthy Caucasian men and women from three independent studies does not support an association between the T111I variant and HDL-C, other plasma lipids, or risk of CHD.
ESTHER : Jensen_2009_Eur.Heart.J_30_1584
PubMedSearch : Jensen_2009_Eur.Heart.J_30_1584
PubMedID: 19411665
Gene_locus related to this paper: human-LIPG

Title : A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis - Brown_2009_J.Lipid.Res_50_1910
Author(s) : Brown RJ , Edmondson AC , Griffon N , Hill TB , Fuki IV , Badellino KO , Li M , Wolfe ML , Reilly MP , Rader DJ
Ref : J Lipid Res , 50 :1910 , 2009
Abstract : Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. EL displays a preference to hydrolyze lipids in HDL. We report here that a naturally occurring low frequency coding variant in the EL gene (LIPG), glycine-26 to serine (G26S), is significantly more common in African-American individuals with elevated HDL cholesterol (HDL-C) levels. To test the hypothesis that this variant results in reduced EL function, we extensively characterized and compared the catalytic and noncatalytic functions of the G26S variant and wild-type (WT) EL. While the catalytic-specific activity of G26S EL is similar to WT EL, its secretion is markedly reduced. Consistent with this observation, we found that carriers of the G26S variant had significantly reduced plasma levels of EL protein. Thus, this N-terminal variant results in reduced secretion of EL protein, plausibly leading to increased HDL-C levels.
ESTHER : Brown_2009_J.Lipid.Res_50_1910
PubMedSearch : Brown_2009_J.Lipid.Res_50_1910
PubMedID: 19411705
Gene_locus related to this paper: human-LIPG

Title : Identification of the active form of endothelial lipase, a homodimer in a head-to-tail conformation - Griffon_2009_J.Biol.Chem_284_23322
Author(s) : Griffon N , Jin W , Petty TJ , Millar J , Badellino KO , Saven JG , Marchadier DH , Kempner ES , Billheimer J , Glick JM , Rader DJ
Ref : Journal of Biological Chemistry , 284 :23322 , 2009
Abstract : Endothelial lipase (EL) is a member of a subfamily of lipases that act on triglycerides and phospholipids in plasma lipoproteins, which also includes lipoprotein lipase and hepatic lipase. EL has a tropism for high density lipoprotein, and its level of phospholipase activity is similar to its level of triglyceride lipase activity. Inhibition or loss-of-function of EL in mice results in an increase in high density lipoprotein cholesterol, making it a potential therapeutic target. Although hepatic lipase and lipoprotein lipase have been shown to function as homodimers, the active form of EL is not known. In these studies, the size and conformation of the active form of EL were determined. Immunoprecipitation experiments suggested oligomerization. Ultracentrifugation experiments showed that the active form of EL had a molecular weight higher than the molecular weight of a simple monomer but less than a dimer. A construct encoding a covalent head-to-tail homodimer of EL (EL-EL) was expressed and had similar lipolytic activity to EL. The functional molecular weights determined by radiation inactivation were similar for EL and the covalent homodimer EL-EL. We previously showed that EL could be cleaved by proprotein convertases, such as PC5, resulting in loss of activity. In cells overexpressing PC5, the covalent homodimeric EL-EL appeared to be more stable, with reduced cleavage and conserved lipolytic activity. A comparative model obtained using other lipase structures suggests a structure for the head-to-tail EL homodimer that is consistent with the experimental findings. These data confirm the hypothesis that EL is active as a homodimer in head-to-tail conformation.
ESTHER : Griffon_2009_J.Biol.Chem_284_23322
PubMedSearch : Griffon_2009_J.Biol.Chem_284_23322
PubMedID: 19567873

Title : Endothelial lipase is increased in vivo by inflammation in humans - Badellino_2008_Circulation_117_678
Author(s) : Badellino KO , Wolfe ML , Reilly MP , Rader DJ
Ref : Circulation , 117 :678 , 2008
Abstract : BACKGROUND: Endothelial lipase (EL) is a plasma lipase that we previously reported to be significantly correlated with all features of the metabolic syndrome in humans, including directly with measures of adiposity and inversely with high-density lipoprotein cholesterol levels. We hypothesized that inflammation associated with obesity results in upregulation of EL. We determined the relationship between inflammatory markers and EL levels in a cohort of healthy persons recruited on the basis of family history of coronary disease. Furthermore, we directly tested the hypothesis that plasma EL concentrations would increase with induction of an inflammatory state by low-dose endotoxin in humans. METHODS AND
RESULTS: High-sensitivity C-reactive protein, interleukin 6, soluble tumor necrosis factor receptor II, soluble intercellular adhesion molecule 1, leptin, and adiponectin were measured in plasma of 858 subjects. Significant direct correlations (P<0.001 for all) were found between EL concentrations and high-sensitivity C-reactive protein (r=0.28), interleukin-6 (r=0.22), soluble tumor necrosis factor receptor II (r=0.22), soluble intercellular adhesion molecule 1 (r=0.24), and leptin (r=0.20). An inverse correlation was present with adiponectin (r=-0.15, P<0.001). Adiponectin inhibited the tumor necrosis factor-alpha-stimulated EL secretion from cultured human coronary endothelial cells in a dose-dependent manner. Experimental low-dose endotoxemia in 20 subjects resulted in a 2.5-fold increase in EL concentrations 12 to 16 hours after injection, which correlated temporally with decreases in both total and high-density lipoprotein phospholipid.
CONCLUSIONS: In humans, plasma inflammatory markers are directly correlated with plasma EL concentrations, and experimental endotoxemia significantly increases plasma EL concentrations, proving that EL is upregulated by inflammation in humans. This mechanism may partially explain the low high-density lipoprotein cholesterol levels seen in obesity and metabolic syndrome.
ESTHER : Badellino_2008_Circulation_117_678
PubMedSearch : Badellino_2008_Circulation_117_678
PubMedID: 18212282

Title : Glycosylation of endothelial lipase at asparagine-116 reduces activity and the hydrolysis of native lipoproteins in vitro and in vivo - Brown_2007_J.Lipid.Res_48_1132
Author(s) : Brown RJ , Miller GC , Griffon N , Long CJ , Rader DJ
Ref : J Lipid Res , 48 :1132 , 2007
Abstract : We previously identified that four of five putative N-linked glycosylation sites of human endothelial lipase (EL) are utilized and suggested that the substitution of asparagine-116 (Asn-116) with alanine (Ala) (N116A) increased the hydrolytic activity of EL. The current study demonstrates that mutagenesis of either Asn-116 to threonine (Thr) or Thr-118 to Ala also disrupted the glycosylation of EL and enhanced catalytic activity toward synthetic substrates by 3-fold versus wild-type EL. Furthermore, we assessed the hydrolysis of native lipoprotein lipids by EL-N116A. EL-N116A exhibited a 5-fold increase in LDL hydrolysis and a 1.8-fold increase in HDL2 hydrolysis. Consistent with these observations, adenovirus-mediated expression of EL-N116A in mice significantly reduced the levels of both LDL and HDL cholesterol beyond the reductions observed by the expression of wild-type EL alone. Finally, we introduced Asn-116 of EL into the analogous positions within LPL and HL, resulting in N-linked glycosylation at this site. Glycosylation at this site suppressed the LPL hydrolysis of synthetic substrates, LDL, HDL2, and HDL3 but had little effect on HL activity. These data suggest that N-linked glycosylation at Asn-116 reduces the ability of EL to hydrolyze lipids in LDL and HDL2.
ESTHER : Brown_2007_J.Lipid.Res_48_1132
PubMedSearch : Brown_2007_J.Lipid.Res_48_1132
PubMedID: 17322565

Title : Upregulation of macrophage endothelial lipase by toll-like receptors 4 and 3 modulates macrophage interleukin-10 and -12 production - Wang_2007_Circ.Res_100_1008
Author(s) : Wang X , Jin W , Rader DJ
Ref : Circulation Research , 100 :1008 , 2007
Abstract : Limited data suggest that endothelial lipase (EL) is synthesized not only by endothelial cells but also by macrophages. Previous studies showed that proinflammatory cytokines upregulate EL in endothelial cells, but there are very few data regarding EL expression, regulation, and functional consequences in macrophages. In the present study, RAW cells and mouse peritoneal macrophages were treated with Toll-like receptor (TLR) ligands and EL expression and its consequences were assessed. We demonstrate that lipopolysaccharide, a TLR4 ligand; and polyinosinic:polycytidylic acid (poly I:C), a TLR3 ligand; but not lipoteichoic acid, a TLR2 ligand, upregulate macrophage EL expression both ex vivo and in vivo. In contrast, macrophage lipoprotein lipase expression is significantly repressed by lipopolysaccharide or poly I:C. Using C3HJ and TLR3 knockout mice, we further show that upregulation of macrophage EL expression by lipopolysaccharide or poly I:C is TLR4 or TLR3 dependent, respectively. Furthermore, we demonstrate that lipopolysaccharide induced interleukin (IL)-10 production was significantly reduced, whereas IL-12 production is significantly increased in J744 macrophages and mouse peritoneal macrophages overexpressing human EL. Conversely, significantly increased IL-10 and significantly decreased IL-12 expression were observed in mouse peritoneal macrophages isolated from EL knockout mice. Finally we show that the catalytic activity is required for EL to modulate the balance of macrophage IL-10 and IL-12 production. These results suggest that macrophage EL may play important roles in modulating the macrophage inflammatory response through local hydrolysis of HDL.
ESTHER : Wang_2007_Circ.Res_100_1008
PubMedSearch : Wang_2007_Circ.Res_100_1008
PubMedID: 17347473

Title : N-Glycosylation regulates endothelial lipase-mediated phospholipid hydrolysis in apoE- and apoA-I-containing high density lipoproteins - Skropeta_2007_J.Lipid.Res_48_2047
Author(s) : Skropeta D , Settasatian C , McMahon MR , Shearston K , Caiazza D , McGrath KC , Jin W , Rader DJ , Barter PJ , Rye KA
Ref : J Lipid Res , 48 :2047 , 2007
Abstract : Endothelial lipase (EL) is a member of the triglyceride lipase gene family with high phospholipase and low triacylglycerol lipase activities and a distinct preference for hydrolyzing phospholipids in HDL. EL has five potential N-glycosylation sites, four of which are glycosylated. The aim of this study was to determine how glycosylation affects the phospholipase activity of EL in physiologically relevant substrates. Site-directed mutants of EL were generated by replacing asparagine (N) 62, 118, 375, and 473 with alanine (A). These glycan-deficient mutants were used to investigate the kinetics of phospholipid hydrolysis in fully characterized preparations of spherical reconstituted high density lipoprotein (rHDL) containing apolipoprotein E2 (apoE2) [(E2)rHDL], apoE3 [(E3)rHDL], apoE4 [(E4)rHDL], or apoA-I [(A-I)rHDL] as the sole apolipoprotein. Wild-type EL hydrolyzed the phospholipids in (A-I)rHDL, (E2)rHDL, (E3)rHDL, and (E4)rHDL to similar extents. The phospholipase activities of EL N118A, EL N375A, and EL N473A were significantly diminished relative to that of wild-type EL, with the greatest reduction being apparent for (E3)rHDL. The phospholipase activity of EL N62A was increased up to 6-fold relative to that of wild-type EL, with the greatest enhancement of activity being observed for (E2)rHDL. These data show that individual N-linked glycans have unique and important effects on the phospholipase activity and substrate specificity of EL.
ESTHER : Skropeta_2007_J.Lipid.Res_48_2047
PubMedSearch : Skropeta_2007_J.Lipid.Res_48_2047
PubMedID: 17545692

Title : Lipases as modulators of atherosclerosis in murine models - Brown_2007_Curr.Drug.Targets_8_1307
Author(s) : Brown RJ , Rader DJ
Ref : Curr Drug Targets , 8 :1307 , 2007
Abstract : Lipoprotein lipase, hepatic lipase, and endothelial lipase are sn-1 lipases that play important roles in the metabolism of plasma lipoproteins. In vitro and in vivo studies suggest that these lipases exhibit both pro- and anti-atherogenic properties, which are dependent primarily on their tissue localization. The following chapter reviews the physiology of these lipases, and the consequences of the loss or gain of function for each lipase in modulating atherosclerosis, with emphasis on murine models.
ESTHER : Brown_2007_Curr.Drug.Targets_8_1307
PubMedSearch : Brown_2007_Curr.Drug.Targets_8_1307
PubMedID: 18220707

Title : High-density lipoprotein hydrolysis by endothelial lipase activates PPARalpha: a candidate mechanism for high-density lipoprotein-mediated repression of leukocyte adhesion - Ahmed_2006_Circ.Res_98_490
Author(s) : Ahmed W , Orasanu G , Nehra V , Asatryan L , Rader DJ , Ziouzenkova O , Plutzky J
Ref : Circulation Research , 98 :490 , 2006
Abstract : Although high-density lipoprotein (HDL) is known to inhibit endothelial adhesion molecule expression, the mechanism for this anti-inflammatory effect remains obscure. Surprisingly, we observed that HDL no longer decreased adhesion of U937 monocytoid cells to tumor necrosis factor (TNF)alpha-stimulated human endothelial cells (EC) in the presence of the general lipase inhibitor tetrahydrolipstatin. In considering endothelial mechanisms responsible for this effect, we found that endothelial lipase (EL) overexpression in both EC and non-EL-expressing NIH/3T3 mouse embryonic fibroblasts cells significantly decreased TNFalpha-induced VCAM1 expression and promoter activity in a manner dependent on HDL concentration and intact EL activity. Given recent evidence for lipolytic activation of peroxisome proliferator-activated receptors (PPARs)-nuclear receptors implicated in metabolism, atherosclerosis, and inflammation-we hypothesized HDL hydrolysis by EL is an endogenous endothelial mechanism for PPAR activation. In both EL-transfected NIH cells and bovine EC, HDL significantly increased PPAR ligand binding domain activation in the order PPAR-alpha> >-gamma>-delta. Moreover, HDL stimulation induced expression of the canonical PPARalpha-target gene acyl-CoA-oxidase (ACO) in a PPARalpha-dependent manner in ECs. Conditioned media from EL-adenovirus transfected cells but not control media exposed to HDL also activated PPARalpha. PPARalpha activation by EL was most potent with HDL as a substrate, with lesser effects on LDL and VLDL. Finally, HDL inhibited leukocyte adhesion to TNFalpha-stimulated ECs isolated from wild-type but not PPARalpha-deficient mice. This data establishes HDL hydrolysis by EL as a novel, distinct natural pathway for PPARalpha activation and identifies a potential mechanism for HDL-mediated repression of VCAM1 expression, with significant implications for both EL and PPARs in inflammation and vascular biology.
ESTHER : Ahmed_2006_Circ.Res_98_490
PubMedSearch : Ahmed_2006_Circ.Res_98_490
PubMedID: 16439686

Title : Visceral adiposity and endothelial lipase - Paradis_2006_J.Clin.Endocrinol.Metab_91_3538
Author(s) : Paradis ME , Badellino KO , Rader DJ , Tchernof A , Richard C , Luu-The V , Deshaies Y , Bergeron J , Archer WR , Couture P , Bergeron N , Lamarche B
Ref : J Clinical Endocrinology Metab , 91 :3538 , 2006
Abstract : CONTEXT: Overexpression of endothelial lipase (EL) has been shown to reduce plasma high-density lipoprotein cholesterol levels in animal models. However, the extent to which EL contributes to modulate the deteriorated high-density lipoprotein profile observed in obesity in humans is less clear. OBJECTIVES: The objectives of this study were to investigate the association between levels of obesity and visceral adiposity in particular and plasma EL concentrations.
METHODS: Postheparin plasma EL concentrations were measured by ELISA and visceral adiposity by computed tomography in a sample of 80 sedentary men in good health. EL mRNA levels in abdominal sc and omental adipose tissues obtained during abdominal hysterectomies were measured in another sample of 14 women.
RESULTS: Plasma EL levels were positively correlated with body mass index (R = 0.46, P < 0.0001), visceral adipose tissue accumulation (R = 0.44, P < 0.0001), and a proatherogenic lipid profile including increased plasma cholesterol and triglycerides. However, EL mRNA levels were similar in sc and omental AT and were 10,000-fold lower than lipoprotein lipase mRNA levels in those tissues.
CONCLUSIONS: Increased visceral adiposity is significantly correlated with elevated plasma EL levels, but this association is unlikely to be causal and may reflect other common metabolic alterations.
ESTHER : Paradis_2006_J.Clin.Endocrinol.Metab_91_3538
PubMedSearch : Paradis_2006_J.Clin.Endocrinol.Metab_91_3538
PubMedID: 16772345

Title : Endothelial lipase concentrations are increased in metabolic syndrome and associated with coronary atherosclerosis - Badellino_2006_PLoS.Med_3_e22
Author(s) : Badellino KO , Wolfe ML , Reilly MP , Rader DJ
Ref : PLoS Med , 3 :e22 , 2006
Abstract : BACKGROUND: Endothelial lipase (EL), a new member of the lipase family, has been shown to modulate high-density lipoprotein (HDL-C) metabolism and atherosclerosis in mouse models. We hypothesized that EL concentrations would be associated with decreased HDL-C and increased atherosclerosis in humans. METHODS AND FINDINGS: Healthy individuals with a family history of premature coronary heart disease (n = 858) were recruited as part of the Study of the Inherited Risk of Atherosclerosis. Blood was drawn in the fasting state before and, in a subgroup (n = 510), after administration of a single dose of intravenous heparin. Plasma lipids were measured enzymatically, lipoprotein subclasses were assessed by nuclear magnetic resonance, and coronary artery calcification (CAC) was quantified by electron beam computed tomography. Plasma EL mass was measured using a newly developed enzyme-linked immunosorbent assay. Median EL mass in pre-heparin plasma was 442 (interquartile range = 324-617) ng/ml. Median post-heparin mass was approximately 3-fold higher, 1,313 (888-1,927) ng/ml. The correlation between pre-heparin EL mass and post-heparin EL mass was 0.46 (p < 0.001). EL mass concentrations in both pre- and post-heparin plasma significantly correlated with all NCEP ATPIII-defined metabolic syndrome factors: waist circumference (r = 0.28 and 0.22, respectively, p < 0.001 for each), blood pressure (r = 0.18 and 0.24, p < 0.001 for each), triglycerides (r = 0.22, p < 0.001; and 0.13, p = 0.004), HDL cholesterol (r = -0.11, p = 0.002; and -0.18, p < 0.001), and fasting glucose (r = 0.11 and 0.16, p = 0.001 for both). EL mass in both routine (odds ratio [OR] = 1.67, p = 0.01) and post-heparin (OR = 2.42, p = 0.003) plasma was associated with CAC as determined by ordinal regression after adjustment for age, gender, waist circumference, vasoactive medications, hormone replacement therapy (women), and established cardiovascular risk factors.
CONCLUSIONS: We report, to our knowledge for the first time, that human plasma EL concentrations, in both post-heparin and routine pre-heparin plasma, are significantly associated with metabolic syndrome features and with subclinical atherosclerosis. EL may be a pro-atherogenic factor in humans, especially in overweight individuals and those with metabolic syndrome.
ESTHER : Badellino_2006_PLoS.Med_3_e22
PubMedSearch : Badellino_2006_PLoS.Med_3_e22
PubMedID: 16354105

Title : Substrate specificity of lipoprotein lipase and endothelial lipase: studies of lid chimeras - Griffon_2006_J.Lipid.Res_47_1803
Author(s) : Griffon N , Budreck EC , Long CJ , Broedl UC , Marchadier DH , Glick JM , Rader DJ
Ref : J Lipid Res , 47 :1803 , 2006
Abstract : The triglyceride (TG) lipase gene subfamily, consisting of LPL, HL, and endothelial lipase (EL), plays a central role in plasma lipoprotein metabolism. Compared with LPL and HL, EL is relatively more active as a phospholipase than as a TG lipase. The amino acid loop or "lid" covering the catalytic site has been implicated as the basis for the difference in substrate specificity between HL and LPL. To determine the role of the lid in the substrate specificity of EL, we studied EL in comparison with LPL by mutating specific residues of the EL lid and exchanging their lids. Mutation studies showed that amphipathic properties of the lid contribute to substrate specificity. Exchanging lids between LPL and EL only partially shifted the substrate specificity of the enzymes. Studies of a double chimera possessing both the lid and the C-terminal domain (C-domain) of EL in the LPL backbone showed that the role of the lid in determining substrate specificity does not depend on the nature of the C-domain of the lipase. Using a kinetic assay, we showed an additive effect of the EL lid on the apparent affinity for HDL(3) in the presence of the EL C-domain.
ESTHER : Griffon_2006_J.Lipid.Res_47_1803
PubMedSearch : Griffon_2006_J.Lipid.Res_47_1803
PubMedID: 16682746

Title : Endothelial lipase is associated with inflammation in humans - Paradis_2006_J.Lipid.Res_47_2808
Author(s) : Paradis ME , Badellino KO , Rader DJ , Deshaies Y , Couture P , Archer WR , Bergeron N , Lamarche B
Ref : J Lipid Res , 47 :2808 , 2006
Abstract : The aim of this study was to investigate the extent to which inflammation is linked with plasma endothelial lipase (EL) concentrations among healthy sedentary men. Plasma C-reactive protein (CRP) concentrations were measured with a highly sensitive commercial immunoassay, plasma interleukin-6 (IL-6) concentrations were measured using a commercial ELISA, and plasma secretory phospholipase A(2) type IIA (sPLA(2)-IIA) concentrations were measured using a commercial assay in a sample of 74 moderately obese men (mean body mass index, 29.8 +/- 5.2 kg/m(2)). Plasma EL concentrations were positively correlated with various indices of obesity, fasting plasma insulin, and plasma CRP, IL-6, and sPLA(2)-IIA concentrations. Multiple regression analyses revealed that plasma CRP concentrations explained 14.5% (P = 0.0008) of the variance in EL concentrations. When entered into the model, LPL activity accounted for 16.1% (P < 0.0001) and plasma CRP concentrations accounted for 20.9% (P < 0.0001) of the variance in EL concentrations. The combined impact of visceral adipose tissue (VAT) and of an inflammation score on EL concentrations was investigated. Among subjects with high or low VAT, those having a high inflammation score based on plasma CRP, IL-6, and sPLA(2)-IIA concentrations had increased plasma EL concentrations (P = 0.0005). In conclusion, our data reveal a strong association between proinflammatory cytokines and plasma EL concentrations among healthy people with low or high VAT levels.
ESTHER : Paradis_2006_J.Lipid.Res_47_2808
PubMedSearch : Paradis_2006_J.Lipid.Res_47_2808
PubMedID: 16980590

Title : Molecular regulation of HDL metabolism and function: implications for novel therapies - Rader_2006_J.Clin.Invest_116_3090
Author(s) : Rader DJ
Ref : J Clinical Investigation , 116 :3090 , 2006
Abstract : HDL metabolism represents a major target for the development of therapies intended to reduce the risk of atherosclerotic cardiovascular disease. HDL metabolism is complex and involves dissociation of HDL apolipoprotein and HDL cholesterol metabolism. Advances in our understanding of the molecular regulation of HDL metabolism, macrophage cholesterol efflux, and HDL function will lead to a variety of novel therapeutics.
ESTHER : Rader_2006_J.Clin.Invest_116_3090
PubMedSearch : Rader_2006_J.Clin.Invest_116_3090
PubMedID: 17143322

Title : Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation - Moore_2005_Circ.Res_97_763
Author(s) : Moore RE , Navab M , Millar JS , Zimetti F , Hama S , Rothblat GH , Rader DJ
Ref : Circulation Research , 97 :763 , 2005
Abstract : To test the hypothesis that apolipoprotein A-I (apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol (HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I-/- mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor-/-/apobec-/- (LA) mice to generate LA mice with apoA-I+/+, apoA-I+/-, and apoA-I-/- genotypes. There were no major differences in the amounts of non-HDL-C and HDL-C in the plasma between different apoA-I genotypes. A significant inverse relationship was observed, however, between apoA-I gene dose and atherosclerosis in both female and male mice. Compared with LA-apoA-I+/+ mice, serum from LA-apoA-I-/- mice had a significantly reduced capacity to function as an acceptor of ABCA1- and SR-BI-mediated cellular cholesterol efflux, and also had markedly reduced lecithin cholesterol acyltransferase activity. In addition, LA-apoA-I-/- mice had significantly reduced macrophage-derived cholesterol esterification and reverse cholesterol transport in vivo. There was significantly reduced plasma paraoxonase (PON-1) activity, impaired HDL vascular antiinflammatory function, and increased basal levels of monocyte chemotactic protein-1 in the plasma of LA-apoA-I-/- mice compared with LA-apoA-I+/+ mice. In LA-apoA-I-/- mice, there was also greater induction of some, but not all, inflammatory cytokines and chemokines in response to intraperitoneal injection of lipopolysaccharide than in LA-apoA-I+/+ mice. We conclude that apoA-I inhibits atherosclerosis by promoting both macrophage reverse cholesterol transport and HDL antiinflammatory function, and that these anti-atherogenic functions of apoA-I are largely independent of the plasma level of HDL-C in this mouse model.
ESTHER : Moore_2005_Circ.Res_97_763
PubMedSearch : Moore_2005_Circ.Res_97_763
PubMedID: 16151025

Title : Regulated expression of endothelial lipase by porcine brain capillary endothelial cells constituting the blood-brain barrier - Sovic_2005_J.Neurochem_94_109
Author(s) : Sovic A , Panzenboeck U , Wintersperger A , Kratzer I , Hammer A , Levak-Frank S , Frank S , Rader DJ , Malle E , Sattler W
Ref : Journal of Neurochemistry , 94 :109 , 2005
Abstract : Normal neurological function depends on a constant supply of polyunsaturated fatty acids to the brain. A considerable proportion of essential fatty acids originates from lipoprotein-associated lipids that undergo uptake and/or catabolism at the blood-brain barrier (BBB). This study aimed at identifying expression and regulation of endothelial lipase (EL) in brain capillary endothelial cells (BCEC), major constituents of the BBB. Our results revealed that BCEC are capable of EL synthesis and secretion. Overexpression of EL resulted in enhanced hydrolysis of extracellular high-density lipoprotein (HDL)-associated sn-2-labeled [(14)C]20 : 4 phosphatidylcholine. [(14)C]20 : 4 was recovered in cellular lipids, indicating re-uptake and intracellular re-esterification. To investigate local regulation of EL in the cerebrovasculature, BCEC were cultured in the presence of peroxisome-proliferator activated receptor (PPAR)- and liver X receptor (LXR)-agonists, known to regulate HDL levels. These experiments revealed that 24(S)OH-cholesterol (a LXR agonist), bezafibrate (a PPARalpha agonist), or pioglitazone (a PPARgamma agonist) resulted in down-regulation of EL mRNA and protein levels. Our findings implicate that EL could generate fatty acids at the BBB for transport to deeper regions of the brain as building blocks for membrane phospholipids. In addition PPAR and LXR agonists appear to contribute to HDL homeostasis at the BBB by regulating EL expression.
ESTHER : Sovic_2005_J.Neurochem_94_109
PubMedSearch : Sovic_2005_J.Neurochem_94_109
PubMedID: 15953354

Title : Endothelial lipase provides an alternative pathway for FFA uptake in lipoprotein lipase-deficient mouse adipose tissue - Kratky_2005_J.Clin.Invest_115_161
Author(s) : Kratky D , Zimmermann R , Wagner EM , Strauss JG , Jin W , Kostner GM , Haemmerle G , Rader DJ , Zechner R
Ref : J Clinical Investigation , 115 :161 , 2005
Abstract : Lipoprotein lipase (LPL) is thought to be the only enzyme responsible for the catabolism of triglycerides (TGs) associated with TG-rich lipoproteins in adipose tissue (AT). However, LPL deficiency in humans and induced mutant mice is not associated with decreased fat mass. We investigated whether endothelial lipase (EL), a recently discovered phospholipase, might represent an alternative mechanism for the uptake of phospholipid-derived fatty acids in murine lipoprotein-deficient AT. When LPL was expressed in AT and isolated murine adipocytes, EL mRNA was not detectable. In contrast, mouse AT and isolated adipocytes that lacked LPL expressed large amounts of EL mRNA. The cellular phospholipase activity in LPL-deficient fat pads was increased 4-fold compared with control fat pads and could be inhibited to control levels by a specific EL antibody. Fatty acids produced by EL activity were absorbed by adipocytes and incorporated into the TG moiety of AT. Our results suggest that EL activity in AT and other peripheral tissues might contribute to the tissue uptake of free fatty acids, which could have important implications for the metabolism of plasma lipoproteins.
ESTHER : Kratky_2005_J.Clin.Invest_115_161
PubMedSearch : Kratky_2005_J.Clin.Invest_115_161
PubMedID: 15630456

Title : Evidence that endothelial lipase remodels high density lipoproteins without mediating the dissociation of apolipoprotein A-I - Jahangiri_2005_J.Lipid.Res_46_896
Author(s) : Jahangiri A , Rader DJ , Marchadier D , Curtiss LK , Bonnet DJ , Rye KA
Ref : J Lipid Res , 46 :896 , 2005
Abstract : Endothelial lipase (EL) is a triglyceride lipase gene family member that has high phospholipase and low triglyceride lipase activity. The aim of this study was to determine whether the phospholipase activity of EL is sufficient to remodel HDLs into small particles and mediate the dissociation of apolipoprotein A-I (apoA-I). Spherical, reconstituted HDLs (rHDLs) containing apoA-I only [(A-I)rHDLs], apoA-II only [(A-II)rHDLs], or both apoA-I and apoA-II [(A-I/A-II) rHDLs] were prepared. The rHDLs, which contained only cholesteryl esters in their core and POPC on the surface, were incubated with EL. As the rHDLs did not contain triacylglycerol, only the POPC was hydrolyzed. Hydrolysis was greater in the (A-I/A-II)rHDLs than in the (A-I)rHDLs. The (A-II)rHDL phospholipids were not hydrolyzed by EL. EL remodeled the (A-I)rHDLs and (A-I/A-II)rHDLs, but not the (A-II)rHDLs, into smaller particles. The reduction in particle size was related to the amount of phospholipid hydrolysis, with the diameter of the (A-I/A-II)rHDLs decreasing more than that of the (A-I)rHDLs. These changes did not affect the conformation of apoA-I, and neither apoA-I nor apoA-II dissociated from the rHDLs. Comparable results were obtained when human plasma HDLs were incubated with EL. These results establish that the phospholipase activity of EL remodels plasma HDLs and rHDLs into smaller particles without mediating the dissociation of apolipoproteins.
ESTHER : Jahangiri_2005_J.Lipid.Res_46_896
PubMedSearch : Jahangiri_2005_J.Lipid.Res_46_896
PubMedID: 15687350

Title : Tissue-specific expression pattern of human endothelial lipase in transgenic mice - Broedl_2005_Atherosclerosis_181_271
Author(s) : Broedl UC , Jin W , Marchadier D , Secreto A , Rader DJ
Ref : Atherosclerosis , 181 :271 , 2005
Abstract : Endothelial lipase (EL), a new member of the triacylglycerol lipase gene family, is a key enzyme in HDL metabolism. The EL expression pattern in humans was reported to be unique and complementary to that documented for lipoprotein lipase. The regulatory elements responsible for the tissue-specific EL expression are not identified yet. In order to confine these sequences to a defined region of the EL promoter, we analyzed EL mRNA expression in human EL transgenic mice expressing EL under the control of the endogenous human promoter. We identified small intestine, mammary gland, adipose tissue and the adrenal gland as previously unknown tissues to express EL. Our data demonstrate that regulatory elements within 11.4 kb of 5' and 9.9 kb of 3' human EL flanking region promote the expression of EL in small intestine, ovary, testis, mammary gland, brain, lung, aorta, adipose tissue and the adrenals, whereas regulatory sequences located between 27.4 and 11.4 kb of 5' or 9.9 and 48.7 kb of 3' human EL flanking region seem to be responsible for kidney-specific EL expression.
ESTHER : Broedl_2005_Atherosclerosis_181_271
PubMedSearch : Broedl_2005_Atherosclerosis_181_271
PubMedID: 16039280

Title : Higher order lipase gene association with plasma triglycerides - Reilly_2005_J.Lipid.Res_46_1914
Author(s) : Reilly MP , Foulkes AS , Wolfe ML , Rader DJ
Ref : J Lipid Res , 46 :1914 , 2005
Abstract : Lipoprotein lipase, HL, and endothelial lipase (EL) are proteoglycan-bound enzymes that regulate plasma lipoprotein levels through coordinated triglyceride (TG) lipase and phospholipase activity. We hypothesized that single nucleotide polymorphisms (SNPs) in lipase genes would have higher order impact on plasma lipoproteins beyond the influence of individual SNPs. In a sample of asymptomatic Caucasian subjects (n = 738), we used a two-stage approach, first identifying groups of subjects with similar multilocus lipase genotypes and then characterizing the relationships between genotype groups and plasma lipids. Using complementary methods, including a permutation test procedure and a mixed-effects modeling approach, we found a higher order interaction between four SNPs in three lipase genes (EL 2,237 3' untranslated region, EL Thr111Ile, HL -514C/T, and LPL HindIII) and plasma TG levels. Subjects who were heterozygous for all four lipase SNPs had significantly higher plasma TG levels beyond the effect of individual lipase SNPs and environmental factors, even after correcting for multiple comparisons. In conclusion, lipase genes had synergistic association with plasma TG beyond individual gene effects. Higher order multilocus genotype contributions to dyslipidemia and atherosclerotic cardiovascular disease need to be considered a priori because they may have an important effect even in the absence of significant main effects of the individual genes.
ESTHER : Reilly_2005_J.Lipid.Res_46_1914
PubMedSearch : Reilly_2005_J.Lipid.Res_46_1914
PubMedID: 15961789

Title : Gene therapy for genetic lipid disorders: lipoprotein lipase deficiency as a paradigm -
Author(s) : Rader DJ
Ref : Neth J Med , 63 :2 , 2005
PubMedID: 15719845

Title : Gain-of-function mutations and therapeutic implications: lipoprotein lipase S447X to the rescue -
Author(s) : Rader DJ
Ref : Arterioscler Thromb Vasc Biol , 25 :2018 , 2005
PubMedID: 16199757

Title : Proprotein convertases [corrected] are responsible for proteolysis and inactivation of endothelial lipase - Jin_2005_J.Biol.Chem_280_36551
Author(s) : Jin W , Fuki IV , Seidah NG , Benjannet S , Glick JM , Rader DJ
Ref : Journal of Biological Chemistry , 280 :36551 , 2005
Abstract : Plasma lipoprotein metabolism is tightly regulated by several members of the triglyceride lipase family, including endothelial lipase (EL) and lipoprotein lipase (LPL). Our previous work suggested that EL is proteolytically processed. In this report, we have used a combination of epitope tagging, mutagenesis, and N-terminal sequencing to determine the precise location of the cleavage site within EL. The cleavage occurs immediately after the sequence RNKR, a known recognition sequence for the proprotein convertase (PC) family. We demonstrate that some PCs, but not all, can proteolytically cleave EL at this site and thereby directly regulate EL enzymatic activity through modulating EL cleavage. Furthermore, specific knockdown of individual PCs proves that PCs are the proteases that cleave EL in human endothelial cells. Interestingly, a homologous site in LPL is also cleaved by PCs. This action is unusual for PCs, which are traditionally known as activators of pro-proteins, and highlights a potential role of PCs in lipid metabolism through their proteolytic processing of lipases.
ESTHER : Jin_2005_J.Biol.Chem_280_36551
PubMedSearch : Jin_2005_J.Biol.Chem_280_36551
PubMedID: 16109723

Title : Structural basis of endothelial lipase tropism for HDL - Broedl_2004_FASEB.J_18_1891
Author(s) : Broedl UC , Jin W , Fuki IV , Glick JM , Rader DJ
Ref : FASEB Journal , 18 :1891 , 2004
Abstract : Lipoprotein lipase (LPL) and endothelial lipase (EL), the most closely related enzymes among the members of the triglyceride lipase gene family with regard to primary sequence, have distinct lipolytic properties (triglyceride lipase vs. phospholipase) as well as different preferences for specific types of lipoproteins [triglyceride-rich lipoproteins vs. high density lipoprotein (HDL)] Lipid substrate specificity is believed to be conferred by the lid region located in the amino-terminal domain of the enzymes, whereas surprisingly little work has been done to identify the region mediating lipoprotein substrate specificity. To determine the domain responsible for lipoprotein preference within each enzyme, we generated the domain chimeric enzyme LPL-EL. The heterologous carboxy-terminal (C terminal) domain did not change lipid substrate preference (triglyceride vs. phospholipase) as determined by using artificial substrates. The EL C-terminal domain, however, enabled LPL-EL to bridge HDL particles like wild-type EL, whereas LPL only mediated binding of very low density lipoprotein. Unlike wild-type LPL, LPL-EL had substantial ability to hydrolyze HDL lipids similar to that of wild-type EL. Overexpression of LPL-EL in wild-type mice resulted in significantly reduced levels of HDL cholesterol and phospholipids by 93 and 85%, respectively, similar to the extent seen in EL-expressing mice, whereas no reduction of these parameters was observed in LPL-expressing mice. We conclude that the C-terminal domain of EL is crucial for the ability of EL to bind and to hydrolyze HDL and converts LPL to an enzyme fully capable of hydrolyzing HDL, highlighting the importance of the C-terminal lipase domain in lipoprotein substrate preference.
ESTHER : Broedl_2004_FASEB.J_18_1891
PubMedSearch : Broedl_2004_FASEB.J_18_1891
PubMedID: 15456739
Gene_locus related to this paper: human-LIPG

Title : The role of endothelial lipase in high-density lipoprotein metabolism - Badellino_2004_Curr.Opin.Cardiol_19_392
Author(s) : Badellino KO , Rader DJ
Ref : Curr Opin Cardiol , 19 :392 , 2004
Abstract : PURPOSE OF REVIEW: Elevating high-density lipoprotein levels is increasingly being identified as an essential strategy for the prevention of atherosclerosis. Plasma levels of high-density lipoprotein cholesterol and its major protein, apoAI, are largely influenced by the rate of turnover. Lipases play an important role in modulating the metabolism of high-density lipoprotein. In particular, endothelial lipase has been shown to be an important determinant of high-density lipoprotein metabolism and levels in murine models. This article reviews new developments in our understanding of the biology of endothelial lipase and its relation to high-density lipoprotein metabolism. RECENT FINDINGS: Inhibition of the endothelial lipase gene, either by antibody injection or by targeted gene deletion, results in an approximately 50% increase in high-density lipoprotein cholesterol levels in mice. As many as 31 single-nucleotide polymorphisms have been identified in the endothelial lipase gene. The 584 C/T mutation, which results in a threonine-to-isoleucine amino acid change, has been associated with higher high-density lipoprotein cholesterol levels in three separate studies. SUMMARY: Increasing evidence suggests that endothelial lipase plays a significant role in high-density lipoprotein metabolism. Endothelial lipase could be an important new target for novel therapies to raise high-density lipoprotein levels.
ESTHER : Badellino_2004_Curr.Opin.Cardiol_19_392
PubMedSearch : Badellino_2004_Curr.Opin.Cardiol_19_392
PubMedID: 15218402

Title : Endothelial lipase: a modulator of lipoprotein metabolism upregulated by inflammation - Broedl_2004_Trends.Cardiovasc.Med_14_202
Author(s) : Broedl UC , Jin W , Rader DJ
Ref : Trends Cardiovasc Med , 14 :202 , 2004
Abstract : Both acute and chronic inflammatory states are associated with decreased levels of high-density lipoprotein (HDL) cholesterol, yet the underlying mechanism is poorly understood. Endothelial lipase (EL), a recently described member of the triglyceride lipase family, has been shown to be a key enzyme in HDL metabolism. Expression of EL by endothelial cells is upregulated by proinflammatory cytokines and is associated with increased EL-specific triglyceride and phospholipase activity in vitro. Thus, EL may play an important role in lipid metabolism and energy homeostasis in states of acute and chronic inflammation.
ESTHER : Broedl_2004_Trends.Cardiovasc.Med_14_202
PubMedSearch : Broedl_2004_Trends.Cardiovasc.Med_14_202
PubMedID: 15261893
Gene_locus related to this paper: human-LIPG

Title : Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins - Broedl_2004_Circ.Res_94_1554
Author(s) : Broedl UC , Maugeais C , Millar JS , Jin W , Moore RE , Fuki IV , Marchadier D , Glick JM , Rader DJ
Ref : Circulation Research , 94 :1554 , 2004
Abstract : Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are "HDL animals" and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor-deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (ELS149A); unexpectedly, expression of ELS149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive ELS149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.
ESTHER : Broedl_2004_Circ.Res_94_1554
PubMedSearch : Broedl_2004_Circ.Res_94_1554
PubMedID: 15117821

Title : Dose-dependent acceleration of high-density lipoprotein catabolism by endothelial lipase - Maugeais_2003_Circulation_108_2121
Author(s) : Maugeais C , Tietge UJ , Broedl UC , Marchadier D , Cain W , McCoy MG , Lund-Katz S , Glick JM , Rader DJ
Ref : Circulation , 108 :2121 , 2003
Abstract : BACKGROUND: Factors that regulate the metabolism of HDL and apolipoprotein A-I (apoA-I) are incompletely understood. Overexpression of endothelial lipase (EL) markedly reduces plasma levels of HDL cholesterol and apoA-I in mice, but the mechanisms of this effect remain unknown. METHODS AND RESULTS: We used different doses of a recombinant adenoviral vector to overexpress human EL in mice and studied the effects on plasma phospholipase activity, plasma lipids, HDL particle size, HDL turnover, and tissue sites of HDL degradation in mice. Overexpression of EL was associated with a significant dose-dependent increase in postheparin plasma phospholipase activity. Plasma phospholipid, HDL cholesterol, and apoA-I levels were markedly decreased, even at the lowest dose of vector. Kinetic studies demonstrated a significant dose-dependent increase in the fractional catabolic rate of HDL-apolipoprotein in EL-overexpressing mice. The postheparin plasma phospholipase activity was significantly positively correlated with HDL-apolipoprotein fractional catabolic rate. The uptake of apoA-I by the kidney and the liver was significantly increased by 2.5-fold and 3-fold, respectively, in mice overexpressing EL. CONCLUSIONS: Expression of EL in mice results in a dose-dependent increase in postheparin plasma phospholipase activity, catabolic rate of HDL-apolipoprotein, and uptake of apoA-I in both kidney and liver.
ESTHER : Maugeais_2003_Circulation_108_2121
PubMedSearch : Maugeais_2003_Circulation_108_2121
PubMedID: 14517167

Title : Evidence that hepatic lipase and endothelial lipase have different substrate specificities for high-density lipoprotein phospholipids - Duong_2003_Biochemistry_42_13778
Author(s) : Duong M , Psaltis M , Rader DJ , Marchadier D , Barter PJ , Rye KA
Ref : Biochemistry , 42 :13778 , 2003
Abstract : Hepatic lipase (HL) and endothelial lipase (EL) are both members of the triglyceride lipase gene family. HL hydrolyzes phospholipids and triglycerides in triglyceride-rich lipoproteins and high-density lipoproteins (HDL). EL hydrolyzes HDL phospholipids and has low triglyceride lipase activity. The aim of this study was to determine if HL and EL hydrolyze different HDL phospholipids and whether HDL phospholipid composition regulates the interaction of EL and HL with the particle surface. Spherical, reconstituted HDL (rHDL) containing either 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), 1-palmitoyl-2-linoleoylphosphatidylcholine (PLPC), 1-palmitoyl-2-arachidonylphosphatidylcholine (PAPC), or 1-palmitoyl-2-docosahexanoylphosphatidylcholine (PDPC) as the only phospholipid, apolipoprotein A-I as the only apolipoprotein, and either cholesteryl esters (CE) only or mixtures of CE and triolein (TO) in their core were prepared. The rHDL were similar in size and had comparable core lipid/apoA-I molar ratios. The CE-containing rHDL were used to determine the kinetics of HL- and EL-mediated phospholipid hydrolysis. For HL the V(max) of phospholipid hydrolysis for (POPC)rHDL > (PLPC)rHDL approximately (PDPC)rHDL > (PAPC)rHDL, while the K(m)(app) for (POPC)rHDL > (PDPC)rHDL > (PLPC)rHDL > (PAPC)rHDL. For EL the V(max) for (PDPC)rHDL > (PAPC)rHDL > (PLPC)rHDL approximately (POPC)rHDL, while the K(m)(app) for (PAPC)rHDL approximately (PLPC)rHDL > (POPC)rHDL > (PDPC)rHDL. The kinetics of EL- and HL-mediated TO hydrolysis was determined using rHDL that contained TO in their core. For HL the V(max) of TO hydrolysis for (PLPC)rHDL > (POPC)rHDL > (PAPC)rHDL > (PDPC)rHDL, while the K(m)(app) for (PLPC)rHDL > (POPC)rHDL approximately (PAPC)rHDL > (PDPC)rHDL. For EL the V(max) and K(m)(app) for (PAPC)rHDL > (PDPC)rHDL > (PLPC)rHDL > (POPC)rHDL. These results establish that EL and HL have different substrate specificities for rHDL phospholipids and that their interactions with the rHDL surface are regulated by phospholipids.
ESTHER : Duong_2003_Biochemistry_42_13778
PubMedSearch : Duong_2003_Biochemistry_42_13778
PubMedID: 14622025
Gene_locus related to this paper: human-LIPC , human-LIPG

Title : Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo - Jin_2003_J.Clin.Invest_111_357
Author(s) : Jin W , Millar JS , Broedl U , Glick JM , Rader DJ
Ref : J Clinical Investigation , 111 :357 , 2003
Abstract : Endothelial lipase (EL) is a recently discovered member of the lipoprotein lipase gene family that hydrolyzes HDL phospholipids ex vivo and reduces HDL cholesterol (HDL-C) levels when overexpressed in vivo in mice. To gain further insight into the physiological role of EL in the metabolism of HDL in vivo, studies were performed in which EL was inhibited in wild-type, hepatic lipase knockout (HL(-/-)), and human apoA-I transgenic mice by intravenous infusion of a polyclonal antibody inhibitory to murine EL. As compared with infusion of a control antibody, infusion of the inhibitory antibody resulted in a 25-60% increase in HDL-C levels in the three mouse models, with the peak HDL-C levels occurring at 48 hours after injection. Inhibition of EL also generated larger HDL particles in the HL(-/-) mice. The clearance of HDL phospholipid was significantly slower in human apoA-I transgenic mice injected with an antibody against murine EL (mEL) than in mice injected with a control antibody. We conclude that inhibition of EL results in increased HDL-C levels and that EL is an important enzyme in the physiological regulation of HDL metabolism.
ESTHER : Jin_2003_J.Clin.Invest_111_357
PubMedSearch : Jin_2003_J.Clin.Invest_111_357
PubMedID: 12569161

Title : Endogenously produced endothelial lipase enhances binding and cellular processing of plasma lipoproteins via heparan sulfate proteoglycan-mediated pathway - Fuki_2003_J.Biol.Chem_278_34331
Author(s) : Fuki IV , Blanchard N , Jin W , Marchadier DH , Millar JS , Glick JM , Rader DJ
Ref : Journal of Biological Chemistry , 278 :34331 , 2003
Abstract : Endothelial lipase (EL) is a new member of the triglyceride lipase gene family, which includes lipoprotein lipase (LpL) and hepatic lipase (HL). Enzymatic activity of EL has been studied before. Here we characterized the ability of EL to bridge lipoproteins to the cell surface. Expression of EL in wild-type Chinese hamster ovary (CHO)-K1 but not in heparan sulfate proteoglycan (HSPG)-deficient CHO-677 cells resulted in 3-4.4-fold increases of 125I-low density lipoprotein (LDL) and 125I-high density lipoprotein 3 binding (HDL3). Inhibition of proteoglycan sulfation by sodium chlorate or incubation of cells with labeled lipoproteins in the presence of heparin (100 microg/ml) abolished bridging effects of EL. An enzymatically inactive EL, EL-S149A, was equally effective in facilitating lipoprotein bridging as native EL. Processing of LDL and HDL differed notably after initial binding via EL to the cell surface. More than 90% of the surface-bound 125I-LDL was destined for internalization and degradation, whereas about 70% of the surface-bound 125I-HDL3 was released back into the medium. These differences were significantly attenuated after HDL clustering was promoted using antibody against apolipoprotein A-I. At equal protein concentration of added lipoproteins the ratio of HDL3 to VLDL bridging via EL was 0.092 compared with 0.174 via HL and 0.002 via LpL. In summary, EL mediates binding and uptake of plasma lipoproteins via a process that is independent of its enzymatic activity, requires cellular heparan sulfate proteoglycans, and is regulated by ligand clustering.
ESTHER : Fuki_2003_J.Biol.Chem_278_34331
PubMedSearch : Fuki_2003_J.Biol.Chem_278_34331
PubMedID: 12810721
Gene_locus related to this paper: human-LIPG

Title : Identification of genetic variants in endothelial lipase in persons with elevated high-density lipoprotein cholesterol - deLemos_2002_Circulation_106_1321
Author(s) : deLemos AS , Wolfe ML , Long CJ , Sivapackianathan R , Rader DJ
Ref : Circulation , 106 :1321 , 2002
Abstract : BACKGROUND: Elevated high-density lipoprotein cholesterol (HDL-C) is associated with reduced risk of cardiovascular disease, and variation in HDL-C levels has been shown to be approximately 50% heritable. Overexpression of endothelial lipase (EL), a member of the lipoprotein lipase gene family, markedly reduces HDL-C levels in mouse models. We hypothesized that genetic variation in EL might be associated with elevated HDL-C. METHODS AND
RESULTS: All exons and 1.2 kilobase of promoter of the EL gene were sequenced in 20 unrelated human subjects with high HDL-C levels. A total of 17 variants were identified. Six of these were potentially functional and were confirmed by restriction enzyme analysis. Four variants result in amino acid changes (Gly26Ser, Thr111Ile, Thr298Ser, and Asn396Ser,) and 2 variants were in the promoter (-303A/C and -410C/G). The genotype frequencies of each variant were determined in 176 black controls, 165 white controls, and 123 whites with high HDL-C. The Thr111Ile variant was the most common, with an allele frequency of 10.3% in blacks, 31.2% in white controls, and 32.6% in the high HDL-C group. The remaining variants all had allele frequencies <5.0% but differed in frequency among the 3 groups. Interestingly, Gly26Ser, Thr298Ser, and -303A/C were found in the black and high HDL-C white cohorts but were absent in the control white group.
CONCLUSIONS: Six new potentially functional variants in EL were discovered through sequencing of the EL gene in subjects with high HDL-C levels. Differences in allele frequencies exist between blacks and whites and between control subjects and those with high HDL-C levels.
ESTHER : deLemos_2002_Circulation_106_1321
PubMedSearch : deLemos_2002_Circulation_106_1321
PubMedID: 12221047
Gene_locus related to this paper: human-LIPE

Title : Characterization of the lipolytic activity of endothelial lipase - McCoy_2002_J.Lipid.Res_43_921
Author(s) : McCoy MG , Sun GS , Marchadier D , Maugeais C , Glick JM , Rader DJ
Ref : J Lipid Res , 43 :921 , 2002
Abstract : Endothelial lipase (EL) is a new member of the triglyceride lipase gene family previously reported to have phospholipase activity. Using radiolabeled lipid substrates, we characterized the lipolytic activity of this enzyme in comparison to lipoprotein lipase (LPL) and hepatic lipase (HL) using conditioned medium from cells infected with recombinant adenoviruses encoding each of the enzymes. In the absence of serum, EL had clearly detectable triglyceride lipase activity. Both the triglyceride lipase and phospholipase activities of EL were inhibited in a dose-dependent fashion by the addition of serum. The ratio of triglyceride lipase to phospholipase activity of EL was 0.65, compared with ratios of 24.1 for HL and 139.9 for LPL, placing EL at the opposite end of the lipolytic spectrum from LPL. Neither lipase activity of EL was influenced by the addition of apolipoprotein C-II (apoC-II), indicating that EL, like HL, does not require apoC-II for activation. Like LPL but not HL, both lipase activities of EL were inhibited by 1 M NaCl. The relative ability of EL, versus HL and LPL, to hydrolyze lipids in isolated lipoprotein fractions was also examined using generation of FFAs as an end point. As expected, based on the relative triglyceride lipase activities of the three enzymes, the triglyceride-rich lipoproteins, chylomicrons, VLDL, and IDL, were efficiently hydrolyzed by LPL and HL. EL hydrolyzed HDL more efficiently than the other lipoprotein fractions, and LDL was a poor substrate for all of the enzymes.
ESTHER : McCoy_2002_J.Lipid.Res_43_921
PubMedSearch : McCoy_2002_J.Lipid.Res_43_921
PubMedID: 12032167
Gene_locus related to this paper: human-LIPG

Title : Lipase H, a new member of the triglyceride lipase family synthesized by the intestine - Jin_2002_Genomics_80_268
Author(s) : Jin W , Broedl UC , Monajemi H , Glick JM , Rader DJ
Ref : Genomics , 80 :268 , 2002
Abstract : We report here the molecular cloning of a novel member of the triglyceride lipase family, a 2.4-kb cDNA encoding human lipase H (LIPH) and the mouse ortholog (Liph). The human LIPH cDNA encodes a 451-amino-acid protein with a lipase domain. Mouse Liph shows 85% amino acid identity and 75% nucleotide identity to human LIPH. Human LIPH exhibits 47% identity with phosphatidylserine-specific phospholipase A1 (PS-PLA1) and 46% identity with endothelial lipase (LIPG) and lipoprotein lipase (LPL). LIPH is localized on human chromosome 3q27-q28. Northern blot analysis revealed specific expression of LIPH mRNA in intestine, lung, and pancreas. Lipase H protein was also detected in human intestine. Lipase H is a secreted protein with an apparent molecular weight of 63 kDa. Although several lipid substrates were tested, the lipid substrate of LIPG was not identified. Like the other members of this gene family, LIPH may be involved in lipid and energy metabolism.
ESTHER : Jin_2002_Genomics_80_268
PubMedSearch : Jin_2002_Genomics_80_268
PubMedID: 12213196
Gene_locus related to this paper: human-LIPH , mouse-LIPH

Title : Phenotypic correction of lipid storage and growth arrest in wolman disease fibroblasts by gene transfer of lysosomal acid lipase - Tietge_2001_Hum.Gene.Ther_12_279
Author(s) : Tietge UJ , Sun G , Czarnecki S , Yu Q , Lohse P , Du H , Grabowski GA , Glick JM , Rader DJ
Ref : Hum Gene Therapy , 12 :279 , 2001
Abstract : Wolman disease is a lethal lysosomal storage disease due to deficiency of lysosomal acid lipase (LAL). Wolman disease is characterized by pronounced hepatic involvement while neurological symptoms are uncommon, making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacking LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL). Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-fold above levels in control fibroblasts. Furthermore, 72 hr after infection with AdhLAL there was a dose-dependent correction of the severe lipid storage phenotype of Wolman disease fibroblasts. Electron microscopy confirmed significant correction of the lysosomal lipid storage in AdhLAL-infected Wolman disease fibroblasts at the ultrastructural level. Intravenous injection of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepatic LAL activity, and overexpression of LAL was not associated with toxic side effects. These data demonstrate high-level lysosomal expression of recombinant LAL in vitro and in vivo and show the feasibility of gene therapeutic strategies for the treatment of Wolman disease.
ESTHER : Tietge_2001_Hum.Gene.Ther_12_279
PubMedSearch : Tietge_2001_Hum.Gene.Ther_12_279
PubMedID: 11177564
Gene_locus related to this paper: human-LIPA

Title : Endothelial lipase: a new member of the triglyceride lipase gene family - Rader_2000_Curr.Opin.Lipidol_11_141
Author(s) : Rader DJ , Jaye M
Ref : Curr Opin Lipidol , 11 :141 , 2000
Abstract : The triglyceride lipase gene family plays a central role in intestinal lipid absorption, energy homeostasis, lipoprotein metabolism, and atherosclerosis. A new member of this gene family, termed endothelial lipase, was recently reported. The presence of key functional motifs, the endothelial synthesis, the enzymatic profile, and the in-vivo metabolic effects of endothelial lipase suggest that, like other members of this gene family, endothelial lipase may play a role in energy delivery to tissues and in modulating lipoprotein metabolism, and could impact on atherogenesis.
ESTHER : Rader_2000_Curr.Opin.Lipidol_11_141
PubMedSearch : Rader_2000_Curr.Opin.Lipidol_11_141
PubMedID: 10787175

Title : A novel endothelial-derived lipase that modulates HDL metabolism - Jaye_1999_Nat.Genet_21_424
Author(s) : Jaye M , Lynch KJ , Krawiec J , Marchadier D , Maugeais C , Doan K , South V , Amin D , Perrone M , Rader DJ
Ref : Nat Genet , 21 :424 , 1999
Abstract : High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease. At least 50% of the variation in HDL cholesterol levels is genetically determined, but the genes responsible for variation in HDL levels have not been fully elucidated. Lipoprotein lipase (LPL) and hepatic lipase (HL), two members of the triacylglyerol (TG) lipase family, both influence HDL metabolism and the HL (LIPC) locus has been associated with variation in HDL cholesterol levels in humans. We describe here the cloning and in vivo functional analysis of a new member of the TG lipase family. In contrast to other family members, this new lipase is synthesized by endothelial cells in vitro and thus has been termed endothelial lipase (encoded by the LIPG gene). EL is expressed in vivo in organs including liver, lung, kidney and placenta, but not in skeletal muscle. In contrast to LPL and HL, EL has a lid of only 19 residues. EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-I. The endothelial expression, enzymatic profile and in vivo effects of EL suggest that it may have a role in lipoprotein metabolism and vascular biology.
ESTHER : Jaye_1999_Nat.Genet_21_424
PubMedSearch : Jaye_1999_Nat.Genet_21_424
PubMedID: 10192396
Gene_locus related to this paper: human-LIPG

Title : Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease - Rader_1994_J.Clin.Invest_93_321
Author(s) : Rader DJ , Ikewaki K , Duverger N , Schmidt H , Pritchard H , Frohlich J , Clerc M , Dumon MF , Fairwell T , Zech L , Santamarina-Fojo S , Brewer HB, Jr. , et al.
Ref : J Clinical Investigation , 93 :321 , 1994
Abstract : Classic (complete) lecithin:cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal). In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I:A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal). The metabolic basis for the low levels of apoA-II and LpA-I:A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques. The mean plasma residence time of apoA-I was decreased at 2.08 +/- 0.27 d (controls 4.74 +/- 0.65 days); however, the residence time of apoA-II was even shorter at 1.66 +/- 0.24 d (controls 5.25 +/- 0.61 d). In addition, the catabolism of apoA-I in LpA-I:A-II was substantially faster than that of apoA-I in LpA-I. In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II. Because LpA-I has been proposed to be more protective than LpA-I:A-II against atherosclerosis, this selective effect on the metabolism of LpA-I:A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I.
ESTHER : Rader_1994_J.Clin.Invest_93_321
PubMedSearch : Rader_1994_J.Clin.Invest_93_321
PubMedID: 8282802

Title : Two different allelic mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in classic LCAT deficiency: LCAT (tyr83-->stop) and LCAT (tyr156-->asn) - Klein_1993_J.Lipid.Res_34_49
Author(s) : Klein HG , Lohse P , Duverger N , Albers JJ , Rader DJ , Zech LA , Santamarina-Fojo S , Brewer HB, Jr.
Ref : J Lipid Res , 34 :49 , 1993
Abstract : The molecular defects in the lecithin:cholesterol acyltransferase (LCAT) gene have been identified in a 52-year-old patient with classic LCAT deficiency, presenting with corneal clouding and proteinuria. Plasma total cholesterol was normal, triglycerides were elevated, whereas high density lipoprotein (HDL) cholesterol (8 mg/dl) and plasma cholesteryl esters (6% of total cholesterol) were markedly reduced. Plasma cholesterol esterification rate (pCER) was zero, alpha-LCAT activity, assayed using an HDL-like proteoliposome substrate was reduced to 1.6% of control, and LCAT mass was 3.7% of normal plasma levels. DNA sequence analysis of the proband's LCAT gene identified a C to A substitution, converting tyr83 to a stop codon, and a T to A transition, replacing tyr156 by asn. Restriction analysis of PCR-amplified DNA from the proband, a control and his four children using the enzymes Acc I and Rsa I established that the patient is a compound heterozygote for both mutations. The two children, heterozygous for the stop codon defect, were phenotypically indistinguishable from the two with the tyr156 defect. In vitro expression of LCAT (tyr156-->asn) in human embryonic kidney-293 cells established the functional significance of this mutation. The secreted translation product had only 6% of control mass and no detectable CER; however, the residual LCAT mass of the in vitro expressed LCAT (tyr156-->asn) demonstrated a specific alpha-LCAT activity of 30% of control, suggesting that this amino acid substitution results in a mutant enzyme that retains some enzymic activity, but may be rapidly catabolized. In summary, we have identified two unique defects in the LCAT gene that lead to the expression of classic LCAT deficiency in this kindred.
ESTHER : Klein_1993_J.Lipid.Res_34_49
PubMedSearch : Klein_1993_J.Lipid.Res_34_49
PubMedID: 8445342