Lusis AJ

References (42)

Title : NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice - Guo_2021_Sci.Rep_11_16409
Author(s) : Guo F , Seldin M , Peterfy M , Charugundla S , Zhou Z , Lee SD , Mouton A , Rajbhandari P , Zhang W , Pellegrini M , Tontonoz P , Lusis AJ , Shih DM
Ref : Sci Rep , 11 :16409 , 2021
Abstract : We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A beta3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C-C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-beta signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.
ESTHER : Guo_2021_Sci.Rep_11_16409
PubMedSearch : Guo_2021_Sci.Rep_11_16409
PubMedID: 34385484

Title : An integrative systems genetic analysis of mammalian lipid metabolism - Parker_2019_Nature_567_187
Author(s) : Parker BL , Calkin AC , Seldin MM , Keating MF , Tarling EJ , Yang P , Moody SC , Liu Y , Zerenturk EJ , Needham EJ , Miller ML , Clifford BL , Morand P , Watt MJ , Meex RCR , Peng KY , Lee R , Jayawardana K , Pan C , Mellett NA , Weir JM , Lazarus R , Lusis AJ , Meikle PJ , James DE , de Aguiar Vallim TQ , Drew BG
Ref : Nature , 567 :187 , 2019
Abstract : Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.
ESTHER : Parker_2019_Nature_567_187
PubMedSearch : Parker_2019_Nature_567_187
PubMedID: 30814737
Gene_locus related to this paper: human-ABHD1 , mouse-abhd1

Title : Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits - Norheim_2019_Cell.Metab_29_932
Author(s) : Norheim F , Hasin-Brumshtein Y , Vergnes L , Chella Krishnan K , Pan C , Seldin MM , Hui ST , Mehrabian M , Zhou Z , Gupta S , Parks BW , Walch A , Reue K , Hofmann SM , Arnold AP , Lusis AJ
Ref : Cell Metab , 29 :932 , 2019
Abstract : We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet-induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences. Isolated mitochondria showed gene-by-sex interactions in oxidative functions, such that some strains (C57BL/6J) showed similar function between sexes, whereas others (DBA/2J and A/J) showed increased function in females. Reduced adipose mitochondrial function in males as compared to females was associated with increased susceptibility to obesity and insulin resistance. Gonadectomy studies indicated that gonadal hormones acting in a tissue-specific manner were responsible in part for the sex differences.
ESTHER : Norheim_2019_Cell.Metab_29_932
PubMedSearch : Norheim_2019_Cell.Metab_29_932
PubMedID: 30639359
Gene_locus related to this paper: human-LYPLAL1 , mouse-lypl1

Title : Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex - Huang_2013_J.Clin.Invest_123_3815
Author(s) : Huang Y , Wu Z , Riwanto M , Gao S , Levison BS , Gu X , Fu X , Wagner MA , Besler C , Gerstenecker G , Zhang R , Li XM , Didonato AJ , Gogonea V , Tang WH , Smith JD , Plow EF , Fox PL , Shih DM , Lusis AJ , Fisher EA , Didonato JA , Landmesser U , Hazen SL
Ref : J Clinical Investigation , 123 :3815 , 2013
Abstract : Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein-associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr71), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other's function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.
ESTHER : Huang_2013_J.Clin.Invest_123_3815
PubMedSearch : Huang_2013_J.Clin.Invest_123_3815
PubMedID: 23908111

Title : Vasculitis, Atherosclerosis, and Altered HDL Composition in Heme-Oxygenase-1-Knockout Mice - Ishikawa_2012_Int.J.Hypertens_2012_948203
Author(s) : Ishikawa K , Navab M , Lusis AJ
Ref : Int J Hypertens , 2012 :948203 , 2012
Abstract : To elucidate roles of heme oxygenase-1 (HO-1) in cardiovascular system, we have analyzed one-year-old HO-1-knockout mice. Homozygous HO-1-knockout mice had severe aortitis and coronary arteritis with mononuclear cellular infiltration and fatty streak formation even on a standard chow diet. Levels of plasma total cholesterol and HDL were similar among the three genotypes. However, homozygous HO-1-knockout mice had lower body weight and plasma triglyceride. HO-1-deficiency resulted in alteration of the composition of HDL. The ratio of apolipoprotein AI to AII in HO-1-knockout mice was reduced about 10-fold as compared to wild-type mice. In addition, paraoxonase, an enzyme against oxidative stress, was reduced less than 50% in HO-1-knockout mice. The knockout mice also exhibited significant elevation of plasma lipid hydroperoxides. This study using aged HO-1-knockout mice strengthened the idea that HO-1 functions to suppress systemic inflammation in artery wall and prevents plasma lipid peroxidation.
ESTHER : Ishikawa_2012_Int.J.Hypertens_2012_948203
PubMedSearch : Ishikawa_2012_Int.J.Hypertens_2012_948203
PubMedID: 22518297

Title : Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule - Kim_2011_Arterioscler.Thromb.Vasc.Biol_31_2624
Author(s) : Kim JB , Xia YR , Romanoski CE , Lee S , Meng Y , Shi YS , Bourquard N , Gong KW , Port Z , Grijalva V , Reddy ST , Berliner JA , Lusis AJ , Shih DM
Ref : Arterioscler Thromb Vasc Biol , 31 :2624 , 2011
Abstract : OBJECTIVE: Chronic infection has long been postulated as a stimulus for atherogenesis. Pseudomonas aeruginosa infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression. METHODS AND
RESULTS: Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC. CONCLUSION: 3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
ESTHER : Kim_2011_Arterioscler.Thromb.Vasc.Biol_31_2624
PubMedSearch : Kim_2011_Arterioscler.Thromb.Vasc.Biol_31_2624
PubMedID: 21836061

Title : Temporal and tissue-specific patterns of Pon3 expression in mouse: in situ hybridization analysis - Shih_2010_Adv.Exp.Med.Biol_660_73
Author(s) : Shih DM , Xia YR , Yu JM , Lusis AJ
Ref : Advances in Experimental Medicine & Biology , 660 :73 , 2010
Abstract : PON3 is a member of the paraoxonase gene family that includes PON1 and PON2. For example, PON3 and PON1 share approximately 60% identity at the amino acid level. Recent studies have demonstrated that PON3 is present in human and rabbit HDL but not in mouse HDL. Mouse PON3 appears to be cell-associated and is expressed in a wide range of tissues such as liver, adipose, macrophage, and the artery wall. In vitro studies have shown that PON3 can prevent LDL oxidation and destroy bacterial quorum-sensing molecules. Previous studies also showed that human PON3 transgenic mice were protected from obesity and atherosclerosis in both the C57BL/6 J wild-type and LDLR knockout genetic background. Administration of adenovirus expressing the human PON3 gene into apoE -/- mice also decreased atherosclerotic lesion formation. In order to further understand the functions of PON3 in physiology and disease, we performed in situ hybridization analysis to examine Pon3 gene expression patterns in newborn and adult mice, in various tissues, including atherosclerotic lesions of apoE -/- mice. Our results show relatively high levels of Pon3 mRNA labeling in the adrenal gland, submaxillary gland, lung, liver, adipose, pancreas, large intestine, and other tissues of newborn mice. In the adult mouse, Pon3 mRNA levels were much lower in the corresponding tissues as mentioned above for the newborn mouse. Sections of the aortic root from the hearts of both wild-type and apoE -/- mice displayed moderate levels of Pon3 mRNA labeling. Pon3 mRNA was also detected in the atherosclerotic lesion areas at the aortic root of apoE -/- hearts. Our data revealed that mouse Pon3 is expressed in a wide range of tissues, and that its expression is temporally controlled.
ESTHER : Shih_2010_Adv.Exp.Med.Biol_660_73
PubMedSearch : Shih_2010_Adv.Exp.Med.Biol_660_73
PubMedID: 20221872

Title : Chylomicronemia elicits atherosclerosis in mice--brief report - Weinstein_2010_Arterioscler.Thromb.Vasc.Biol_30_20
Author(s) : Weinstein MM , Yin L , Tu Y , Wang X , Wu X , Castellani LW , Walzem RL , Lusis AJ , Fong LG , Beigneux AP , Young SG
Ref : Arterioscler Thromb Vasc Biol , 30 :20 , 2010
Abstract : OBJECTIVE: The risk of atherosclerosis in the setting of chylomicronemia has been a topic of debate. In this study, we examined susceptibility to atherosclerosis in Gpihbp1-deficient mice (Gpihbp1(-/-)), which manifest severe chylomicronemia as a result of defective lipolysis. METHODS AND RESULTS: Gpihbp1(-/-) mice on a chow diet have plasma triglyceride and cholesterol levels of 2812+/-209 and 319+/-27 mg/dL, respectively. Even though nearly all of the lipids were contained in large lipoproteins (50 to 135 nm), the mice developed progressive aortic atherosclerosis. In other experiments, we found that both Gpihbp1-deficient "apo-B48-only" mice and Gpihbp1-deficient "apo-B100-only" mice manifest severe chylomicronemia. Thus, GPIHBP1 is required for the processing of both apo-B48- and apo-B100-containing lipoproteins. CONCLUSIONS: Chylomicronemia causes atherosclerosis in mice. Also, we found that GPIHBP1 is required for the lipolytic processing of both apo-B48- and apo-B100-containing lipoproteins.
ESTHER : Weinstein_2010_Arterioscler.Thromb.Vasc.Biol_30_20
PubMedSearch : Weinstein_2010_Arterioscler.Thromb.Vasc.Biol_30_20
PubMedID: 19815815

Title : The roles of PON1 and PON2 in cardiovascular disease and innate immunity - Shih_2009_Curr.Opin.Lipidol_20_288
Author(s) : Shih DM , Lusis AJ
Ref : Curr Opin Lipidol , 20 :288 , 2009
Abstract : PURPOSE OF REVIEW: The paraoxonase (PON) gene family includes three members, PON1, PON2, and PON3. In-vitro and mouse studies have demonstrated that all three PONs are atheroprotective. Some, but not all, human epidemiologic studies have observed associations between PON gene polymorphisms and risk of cardiovascular disease (CVD). In this review, we summarize studies published within the last year, elucidating involvement of PON1 and PON2 in oxidative stress, CVD, and innate immune responses. RECENT FINDINGS: In a prospective study, the PON1 192QQ genotype and low PON1 activity were associated with increased systemic oxidative stress and increased risk for CVD. PON1 expression protected against Pseudomonas aeruginosa lethality in Drosophila, suggesting that PON1 can interfere with quorum sensing in vivo. PON2 attenuated macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1. Overexpression of PON2 protected against endoplasmic reticulum stress-induced apoptosis when the stress was induced by interference with protein modification but not when endoplasmic reticulum stress was induced by Ca2+ deregulation. SUMMARY: Both mouse and human studies have demonstrated the antioxidative and atheroprotective effects of PON1. The mechanisms by which PON2 exerts its atheroprotective effects are emerging. Large-scale epidemiologic studies are needed to further examine the relationship between PON2 genetic polymorphisms and risk for CVD. Elucidation of the physiologic substrates of the PON proteins is of particular importance to further advance this field.
ESTHER : Shih_2009_Curr.Opin.Lipidol_20_288
PubMedSearch : Shih_2009_Curr.Opin.Lipidol_20_288
PubMedID: 19474728

Title : A common mutation in paraoxonase-2 results in impaired lactonase activity - Stoltz_2009_J.Biol.Chem_284_35564
Author(s) : Stoltz DA , Ozer EA , Recker TJ , Estin M , Yang X , Shih DM , Lusis AJ , Zabner J
Ref : Journal of Biological Chemistry , 284 :35564 , 2009
Abstract : Paraoxonases (PONs) are a family of lactonases with promiscuous enzyme activity that has been implicated in multiple diseases. PON2 is intracellularly located, is the most ubiquitously expressed PON, and has the highest lactonase activity of the PON family members. Whereas some single-nucleotide polymorphisms (SNPs) in PON1 have resulted in altered enzymatic activity in serum, to date the functional consequences of SNPs on PON2 function remain unknown. We hypothesized that a common PON2 SNP would result in impaired lactonase activity. Substitution of cysteine for serine at codon 311 in recombinant PON2 resulted in normal protein production and localization but altered glycosylation and decreased lactonase activity. Moreover, we screened 200 human lung samples for the PON2 Cys(311) variant and found that in vivo this mutation impaired lactonase activity. These data suggest that impaired lactonase activity may play a role in innate immunity, atherosclerosis, and other diseases associated with the PON2 311 SNP.
ESTHER : Stoltz_2009_J.Biol.Chem_284_35564
PubMedSearch : Stoltz_2009_J.Biol.Chem_284_35564
PubMedID: 19840942

Title : Variations in DNA elucidate molecular networks that cause disease - Chen_2008_Nature_452_429
Author(s) : Chen Y , Zhu J , Lum PY , Yang X , Pinto S , MacNeil DJ , Zhang C , Lamb J , Edwards S , Sieberts SK , Leonardson A , Castellini LW , Wang S , Champy MF , Zhang B , Emilsson V , Doss S , Ghazalpour A , Horvath S , Drake TA , Lusis AJ , Schadt EE
Ref : Nature , 452 :429 , 2008
Abstract : Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.
ESTHER : Chen_2008_Nature_452_429
PubMedSearch : Chen_2008_Nature_452_429
PubMedID: 18344982

Title : Decreased obesity and atherosclerosis in human paraoxonase 3 transgenic mice - Shih_2007_Circ.Res_100_1200
Author(s) : Shih DM , Xia YR , Wang XP , Wang SS , Bourquard N , Fogelman AM , Lusis AJ , Reddy ST
Ref : Circulation Research , 100 :1200 , 2007
Abstract : Paraoxonase 3 (PON3) is a member of the PON family, which includes PON1, PON2, and PON3. Recently, PON3 was shown to prevent the oxidation of low-density lipoprotein in vitro. To test the role of PON3 in atherosclerosis and related traits, 2 independent lines of human PON3 transgenic (Tg) mice on the C57BL/6J (B6) background were constructed. Human PON3 mRNA was detected in various tissues, including liver, lung, kidney, brain, adipose, and aorta, of both lines of Tg mice. The human PON3 mRNA levels in the livers of PON3 Tg mice were 4- to 7-fold higher as compared with the endogenous mouse Pon3 mRNA levels. Human PON3 protein and activity were detected in the livers of Tg mice as well. No significant differences in plasma total, high-density lipoprotein, and very-low-density lipoprotein/low-density lipoprotein cholesterol and triglyceride and glucose levels were observed between the PON3 Tg and non-Tg mice. Interestingly, atherosclerotic lesion areas were significantly smaller in both lines of male PON3 Tg mice as compared with the male non-Tg littermates on B6 background fed an atherogenic diet. When bred onto the low-density lipoprotein receptor knockout mouse background, the male PON3 Tg mice also exhibited decreased atherosclerotic lesion areas and decreased expression of monocyte chemoattractant protein-1 in the aorta as compared with the male non-Tg littermates. In addition, decreased adiposity and lower circulating leptin levels were observed in both lines of male PON3 Tg mice as compared with the male non-Tg mice. In an F2 cross, adipose Pon3 mRNA levels inversely correlated with adiposity and related traits. Our study demonstrates that elevated PON3 expression significantly decreases atherosclerotic lesion formation and adiposity in male mice. PON3 may play an important role in protection against obesity and atherosclerosis.
ESTHER : Shih_2007_Circ.Res_100_1200
PubMedSearch : Shih_2007_Circ.Res_100_1200
PubMedID: 17379834

Title : Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia - Stoltz_2007_Am.J.Physiol.Lung.Cell.Mol.Physiol_292_L852
Author(s) : Stoltz DA , Ozer EA , Ng CJ , Yu JM , Reddy ST , Lusis AJ , Bourquard N , Parsek MR , Zabner J , Shih DM
Ref : American Journal of Physiology Lung Cell Mol Physiol , 292 :L852 , 2007
Abstract : Pseudomonas aeruginosa is an important cause of nosocomial infections and is frequently present in the airways of cystic fibrosis patients. Quorum sensing mediates P. aeruginosa's virulence and biofilm formation through density-dependent interbacterial signaling with autoinducers. N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is the major autoinducer in P. aeruginosa. We have previously shown that human airway epithelia and paraoxonases (PONs) degrade 3OC12-HSL. This study investigated the role of PON1, PON2, and PON3 in airway epithelial cell inactivation of 3OC12-HSL. All three PONs were present in murine tracheal epithelial cells, with PON2 and PON3 expressed at the highest levels. Lysates of tracheal epithelial cells from PON2, but not PON1 or PON3, knockout mice had impaired 3OC12-HSL inactivation compared with wild-type mice. In contrast, PON1-, PON2-, or PON3-targeted deletions did not affect 3OC12-HSL degradation by intact epithelia. Overexpression of PON2 enhanced 3OC12-HSL degradation by human airway epithelial cell lysates but not by intact epithelia. Finally, using a quorum-sensing reporter strain of P. aeruginosa, we found that quorum sensing was enhanced in PON2-deficient airway epithelia. In summary, these results show that loss of PON2 impairs 3OC12-HSL degradation by airway epithelial cells and suggests that diffusion of 3OC12-HSL into the airway cells can be the rate-limiting step for degradation of the molecule.
ESTHER : Stoltz_2007_Am.J.Physiol.Lung.Cell.Mol.Physiol_292_L852
PubMedSearch : Stoltz_2007_Am.J.Physiol.Lung.Cell.Mol.Physiol_292_L852
PubMedID: 17122353

Title : Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2 - Ng_2006_J.Biol.Chem_281_29491
Author(s) : Ng CJ , Bourquard N , Grijalva V , Hama S , Shih DM , Navab M , Fogelman AM , Lusis AJ , Young S , Reddy ST
Ref : Journal of Biological Chemistry , 281 :29491 , 2006
Abstract : Paraoxonases (PONs) are a family of proteins that may play a significant role in providing relief from both toxic environmental chemicals as well as physiological oxidative stress. Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases. To determine whether PON2 plays a role in the development of atherosclerosis in vivo, we generated PON2-deficient mice. When challenged with a high fat, high cholesterol diet for 15 weeks, serum levels of high density lipoprotein cholesterol, triglycerides, and glucose were not significantly different between wild-type and PON2-deficient mice. In contrast, serum levels of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) cholesterol were significantly lower (-32%) in PON2-deficient mice compared with wild-type mice. However, despite lower levels of VLDL/LDL cholesterol, mice deficient in PON2 developed significantly larger (2.7-fold) atherosclerotic lesions compared with their wild-type counterparts. Enhanced inflammatory properties of LDL, attenuated anti-atherogenic capacity of high density lipoprotein, and a heightened state of oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages appear to be the main mechanisms behind the larger atherosclerotic lesions in PON2-deficient mice. These results demonstrate that PON2 plays a protective role in atherosclerosis.
ESTHER : Ng_2006_J.Biol.Chem_281_29491
PubMedSearch : Ng_2006_J.Biol.Chem_281_29491
PubMedID: 16891303

Title : Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants - Furlong_2005_Neurotoxicol_26_651
Author(s) : Furlong CE , Cole TB , Jarvik GP , Pettan-Brewer C , Geiss GK , Richter RJ , Shih DM , Tward AD , Lusis AJ , Costa LG
Ref : Neurotoxicology , 26 :651 , 2005
Abstract : Individual differences in detoxication capacities for specific organophosphorous (OP) compounds are due largely to differences in catalytic efficiency or abundance of the HDL-associated enzyme, paraoxonase (PON1). First, we provide evidence that children less than 2 years of age represent a particularly susceptible population for OP exposure due to low abundance of PON1 and variable onset of plasma PON1 activity. Second, we describe studies examining the neurotoxic effects of chronic, low-level OP pesticide exposure in mice. PON1 knockout (PON1(-/-)) and wild-type mice were exposed chronically (PN4 to PN21) to low levels of chlorpyrifos oxon (CPO). Endpoints included cholinesterase activity, histopathology, gene expression, and behavior. Even at PN4, when PON1 levels were low in wild-type mice, PON1(-/-) mice were more sensitive to inhibition of brain cholinesterase by CPO. At PN22, and persisting as long as 4 months, chronic developmental exposure to 0.18 mg/kg/d or 0.25 mg/kg/d CPO resulted in perinuclear vacuolization of cells in a discrete area of the neocortex and irregular distribution of neurons in the cortical plate, with an increase in the number of affected cells at 0.25mg/kg/d. Third, we describe a transgenic mouse model in which human transgenes encoding either hPON1Q192 or hPON1R192 were expressed at equal levels in place of mouse PON1. The developmental onset of expression followed the mouse time course and was identical for the two transgenes, allowing these mice to be used to assess the importance of the Q192R polymorphism during development. Adult mice expressing hPON1R192 were significantly more resistant than hPON1Q192 mice to CPO toxicity. Our studies indicate that children less than 2 years old, especially those homozygous for PON1Q192, would be predicted to be particularly susceptible to CPO toxicity.
ESTHER : Furlong_2005_Neurotoxicol_26_651
PubMedSearch : Furlong_2005_Neurotoxicol_26_651
PubMedID: 16112327

Title : Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism - Cole_2005_Pharmacogenet.Genomics_15_589
Author(s) : Cole TB , Walter BJ , Shih DM , Tward AD , Lusis AJ , Timchalk C , Richter RJ , Costa LG , Furlong CE
Ref : Pharmacogenet Genomics , 15 :589 , 2005
Abstract : OBJECTIVES: The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon.
METHODS: Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPO in vivo. Transgenic mice were generated that expressed either human PON1Q192 or PON1R192 at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure.
RESULTS: Mice expressing PON1Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1R192. The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6-12 h, with PON1R192, PON1Q192, and PON1 mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose-response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. CONCLUSION: These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.
ESTHER : Cole_2005_Pharmacogenet.Genomics_15_589
PubMedSearch : Cole_2005_Pharmacogenet.Genomics_15_589
PubMedID: 16007003

Title : Paraoxonase 1 (PON1) status and risk of insecticide exposure -
Author(s) : Furlong CE , Cole TB , Walter BJ , Shih DM , Tward A , Lusis AJ , Timchalk C , Richter RJ , Costa LG
Ref : J Biochem Mol Toxicol , 19 :182 , 2005
PubMedID: 15977192

Title : Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene - Karlsson_2001_Gene_272_11
Author(s) : Karlsson M , Reue K , Xia YR , Lusis AJ , Langin D , Tornqvist H , Holm C
Ref : Gene , 272 :11 , 2001
Abstract : Monoglyceride lipase (MGL) functions together with hormone-sensitive lipase to hydrolyze intracellular triglyceride stores of adipocytes and other cells to fatty acids and glycerol. In addition, MGL presumably complements lipoprotein lipase in completing the hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides. Cosmid clones containing the mouse MGL gene were isolated from a genomic library using the coding region of the mouse MGL cDNA as probe. Characterization of the clones obtained revealed that the mouse gene contains the coding sequence for MGL on seven exons, including a large terminal exon of approximately 2.6 kb containing the stop codon and the complete 3' untranslated region. Two different 5' leader sequences, diverging 21 bp upstream of the predicted translation initiation codon, were isolated from a mouse adipocyte cDNA library. Western blot analysis of different mouse tissues revealed protein size heterogeneities. The amino acid sequence derived from human MGL cDNA clones showed 84% identity with mouse MGL. The mouse MGL gene was mapped to chromosome 6 in a region with known homology to human chromosome 3q21.
ESTHER : Karlsson_2001_Gene_272_11
PubMedSearch : Karlsson_2001_Gene_272_11
PubMedID: 11470505
Gene_locus related to this paper: human-MGLL , mouse-MGLL

Title : Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids - Reddy_2001_Arterioscler.Thromb.Vasc.Biol_21_542
Author(s) : Reddy ST , Wadleigh DJ , Grijalva V , Ng C , Hama S , Gangopadhyay A , Shih DM , Lusis AJ , Navab M , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 21 :542 , 2001
Abstract : Paraoxonase-1 (PON1) is a secreted protein associated primarily with high density lipoprotein (HDL) and participates in the prevention of low density lipoprotein (LDL) oxidation. Two other paraoxonase (PON) family members, namely, PON2 and PON3, have been identified. In this study, we report the cloning and characterization of the human PON3 gene from HepG2 cells. Tissue Northern analysis identifies an approximately 1.3-kb transcript for PON3 primarily in the liver. PON3-specific peptide antibodies detect an approximately 40-kDa protein associated with HDL and absent from LDL. Pretreatment of cultured human aortic endothelial cells with supernatants from HeLa Tet On cell lines overexpressing PON3 prevents the formation of mildly oxidized LDL and inactivates preformed mildly oxidized LDL. In contrast to PON1, PON3 is not active against the synthetic substrates paraoxon and phenylacetate. Furthermore, PON3 expression is not regulated in HepG2 cells by oxidized phospholipids and is not regulated in the livers of mice fed a high-fat atherogenic diet.
ESTHER : Reddy_2001_Arterioscler.Thromb.Vasc.Biol_21_542
PubMedSearch : Reddy_2001_Arterioscler.Thromb.Vasc.Biol_21_542
PubMedID: 11304470

Title : Genetic and temporal determinants of pesticide sensitivity: role of paraoxonase (PON1) - Furlong_2000_Neurotoxicol_21_91
Author(s) : Furlong CE , Li WF , Richter RJ , Shih DM , Lusis AJ , Alleva E , Costa LG
Ref : Neurotoxicology , 21 :91 , 2000
Abstract : Susceptibility to organophosphorus (OP) insecticides and nerve agents is strongly influenced by genetic and developmental factors. A number of organophosphorothioate insecticides are detoxified in part via a two-step pathway involving bioactivation of the parent compound by the cytochrome P450 systems, then hydrolysis of the resulting oxygenated metabolite (oxon) by serum and liver paraoxonases (PON1). Serum PON1 has been shown to be polymorphic in human populations. The Arg192 isoform (PON1R192) of this HDL-associated protein hydrolyzes paraoxon (POX) at a high rate, while the Gln192 isoform (PON1Q192) hydrolyzes paraoxon at a low rate. The effect of the polymorphism is reversed for the hydrolysis of diazoxon (DZO), soman and particularly sarin. Phenylacetate is hydrolyzed at approximately the same rate by both PON1 isoforms and chlorpyrifos oxon (CPO) slightly faster by the PON1R192 isoform. In addition to the effect of the amino acid substitution on rates of toxicant hydrolysis, two other factors influence these rates. The expression of PON1 is developmentally regulated. Newborns have very low levels of PON1. Adult levels in rats and mice are reached at 3 weeks of age and in humans, sometime after 6 months of age. In addition, among individuals of a given genotype, there is at least a 13-fold difference in expression of PON1 that is stable over time. Dose/response experiments with normal mice injected with purified PON1 and with PON1 knockout mice have clearly demonstrated that the observed differences of in vitro rates of hydrolysis are significant in determining differential sensitivities to specific insecticides processed through the P450/PON1 pathway. Injection of purified rabbit PON1 protects mice from cholinesterase inhibition by chlorpyrifos (CPS) and CPO. Knockout mice are much more sensitive to CPO and DZO than are their PON1+/+ littermates or wild-type mice. A number of recent reports have also indicated that the PON1R192 isoform may be a risk factor for cardiovascular disease. Studies with PON1 knockout mice are also consistent with a role of PON1 in preventing vascular disease.
ESTHER : Furlong_2000_Neurotoxicol_21_91
PubMedSearch : Furlong_2000_Neurotoxicol_21_91
PubMedID: 10794389

Title : Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds - Li_2000_Pharmacogenet_10_767
Author(s) : Li WF , Costa LG , Richter RJ , Hagen T , Shih DM , Tward A , Lusis AJ , Furlong CE
Ref : Pharmacogenetics , 10 :767 , 2000
Abstract : Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-associated esterase that hydrolyzes the toxic metabolites of several organophosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192. Injection of purified PON1 protects animals from OP poisoning. In the present study, we investigated the in-vivo function of PON1 for detoxifying organophosphorus insecticides in PON1-knockout mice that were challenged via dermal exposure with diazoxon, diazinon and paraoxon. PON1-knockout mice were extremely sensitive to diazoxon. Doses (2 and 4 mg/kg) that caused no cholinesterase (ChE) inhibition in wild-type mice were lethal to the knockout mice, which also showed slightly increased sensitivity to the parent compound diazinon. Surprisingly, these knockout mice did not show increased sensitivity to paraoxon. In-vitro assays indicated that the PON1R192 isoform hydrolyzed diazoxon less rapidly than did the PON1Q192 isoform. In-vivo analysis, where PON1-knockout mice received the same amount of either PON1(192) isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1R192 conferred better protection against chlorpyrifos-oxon than PON1Q192. Injection of purified rabbit PON1 or either human PON1(192) isoform did not protect PONI-knockout mice from paraoxon toxicity, nor did over-expression of the human PON1R192 transgene in wild-type mice. Kinetic analysis of the two human PON1(192) isoforms revealed that the catalytic efficiency (Vmax/Km) determines the in-vivo efficacy of PON1 for organophosphorus detoxication. The results indicate that PON1 plays a major role in the detoxication of diazoxon and chlorpyrifos oxon but not paraoxon.
ESTHER : Li_2000_Pharmacogenet_10_767
PubMedSearch : Li_2000_Pharmacogenet_10_767
PubMedID: 11191881

Title : Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages - Escary_1999_J.Lipid.Res_40_397
Author(s) : Escary JL , Choy HA , Reue K , Wang XP , Castellani LW , Glass CK , Lusis AJ , Schotz MC
Ref : J Lipid Res , 40 :397 , 1999
Abstract : Foam cells formed from receptor-mediated uptake of lipoprotein cholesterol by macrophages in the arterial intima are critical in the initiation, progression, and stability of atherosclerotic lesions. Macrophages accumulate cholesterol when conditions favor esterification by acyl-CoA:cholesterol acyltransferase (ACAT) over cholesteryl-ester hydrolysis by a neutral cholesteryl-ester hydrolase, such as hormone-sensitive lipase (HSL), and subsequent cholesterol efflux mediated by extracellular acceptors. We recently made stable transfectants of a murine macrophage cell line, RAW 264.7, that overexpressed a rat HSL cDNA and had a 5-fold higher rate of cholesteryl-ester hydrolysis than control cells. The current study examined the effect of macrophage-specific HSL overexpression on susceptibility to diet-induced atherosclerosis in mice. A transgenic line overexpressing the rat HSL cDNA regulated with a macrophage-specific scavenger receptor promoter-enhancer was established by breeding with C57BL/6J mice. Transgenic peritoneal macrophages exhibited macrophage-specific 7-fold overexpression of HSL cholesterol esterase activity. Total plasma cholesterol levels in transgenic mice fed a chow diet were modestly elevated 16% compared to control littermates. After 14 weeks on a high-fat, high-cholesterol diet, total cholesterol increased 3-fold, with no difference between transgenics and controls. However, HSL overexpression resulted in thicker aortic fatty lesions that were 2.5-times larger in transgenic mice. HSL expression in the aortic lesions was shown by immunocytochemistry. Atherosclerosis was more advanced in transgenic mice exhibiting raised lesions involving the aortic wall, along with lipid accumulation in coronary arteries occurring only in transgenics. Thus, increasing cholesteryl-ester hydrolysis, without concomitantly decreasing ACAT activity or increasing cholesterol efflux, is not sufficient to protect against atherosclerosis. hormone-sensitive lipase overexpression in macrophages.
ESTHER : Escary_1999_J.Lipid.Res_40_397
PubMedSearch : Escary_1999_J.Lipid.Res_40_397
PubMedID: 10064727

Title : Genetically determined susceptibility to organophosphorus insecticides and nerve agents: developing a mouse model for the human PON1 polymorphism - Furlong_1998_Neurotoxicol_19_645
Author(s) : Furlong CE , Li WF , Costa LG , Richter RJ , Shih DM , Lusis AJ
Ref : Neurotoxicology , 19 :645 , 1998
Abstract : Several organophosphorus insecticides and nerve agents are detoxified through the cytochrome P450/paraoxonase (PON1) pathway. PON1 is an HDL-associated enzyme encoded as a 355 amino acid protein in humans. The PON1 Arg192 isoform hydrolyzes paraoxon rapidly while the Gln192 isoform hydrolyzes this compound slowly. Both isoforms hydrolyze phenylacetate and chlorpyrifos oxon at approximately the same rate. We recently found that the effect of this polymorphism is dramatically reversed for sarin hydrolysis. The PON1 Arg192 isoform has virtually no sarinase activity while the Gln192 isoform has substantial activity. The Gln192 isoform also hydrolyzes diazoxon and soman faster than the Arg192 isoform. In addition to the large differences in rates of hydrolysis observed for some OP substrates by the two PON1 isoforms, there is also a large variability in serum PON1 concentrations that is stable over time between individuals. Thus, two factors govern the PON1 status of a given individual, the PON1 genotype as well as the amount of protein expressed from each allele. A two-dimensional enzyme analysis provides an excellent assessment of an individual's PON1 status, ie. the position 192 genotype as well as phenotype, or level of serum PON1 (Nature Genet 14:334-336). Do these interindividual differences in rates of substrate hydrolysis by PON1 reflect an individual's sensitivity or resistance to OP compounds processed through the P450/PON1 pathway? Injection of purified PON1 into mice clearly demonstrates the protective effect of having high serum levels of PON1 against toxicity by chlorpyrifos oxon or chlorpyrifos. Preliminary experiments with PON1 knockout mice, on the other hand, clearly demonstrate that low PON1 levels result in dramatically increased sensitivity to chlorpyrifos oxon. Attempts to express human PON1 in mice from constructs containing either of the human PON1 cDNA sequences were unsuccessful, despite the generation of the respective transgenic mice.
ESTHER : Furlong_1998_Neurotoxicol_19_645
PubMedSearch : Furlong_1998_Neurotoxicol_19_645
PubMedID: 9745924

Title : Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis - Shih_1998_Nature_394_284
Author(s) : Shih DM , Gu L , Xia YR , Navab M , Li WF , Hama S , Castellani LW , Furlong CE , Costa LG , Fogelman AM , Lusis AJ
Ref : Nature , 394 :284 , 1998
Abstract : Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.
ESTHER : Shih_1998_Nature_394_284
PubMedSearch : Shih_1998_Nature_394_284
PubMedID: 9685159

Title : Paraoxonase and coronary heart disease - Mackness_1998_Curr.Opin.Lipidol_9_319
Author(s) : Mackness MI , Mackness B , Durrington PN , Fogelman AM , Berliner J , Lusis AJ , Navab M , Shih DM , Fonarow GC
Ref : Curr Opin Lipidol , 9 :319 , 1998
Abstract : Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. Human PON1 has two genetic polymorphisms giving rise to amino-acid substitutions at positions 55 and 192. The 192 polymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles and coronary heart disease in case-control studies. In recent case-control studies serum PON1 concentration and activity were also found to be decreased in coronary heart disease (CHD) independent of the PON1 polymorphism, and in diabetes serum PON1 specific activity decrease is also independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolysing phospholipid and cholesteryl-ester hydroperoxides.
ESTHER : Mackness_1998_Curr.Opin.Lipidol_9_319
PubMedSearch : Mackness_1998_Curr.Opin.Lipidol_9_319
PubMedID: 9739487

Title : Chromosomal localization of lipolytic enzymes in the mouse: pancreatic lipase, colipase, hormone-sensitive lipase, hepatic lipase, and carboxyl ester lipase - Warden_1993_J.Lipid.Res_34_1451
Author(s) : Warden CH , Davis RC , Yoon MY , Hui DY , Svenson K , Xia YR , Diep A , He KY , Lusis AJ
Ref : J Lipid Res , 34 :1451 , 1993
Abstract : Several lipases and their cofactors are involved in the absorption, transport, storage, and mobilization of lipids. As part of an effort to examine the role of these enzymes in plasma lipid metabolism and genetic susceptibility to atherosclerosis, we report the chromosomal mapping of their genes in mouse. Restriction fragment length variants for each gene were identified, typed in an interspecific cross, and tested for linkage to known chromosomal markers. The gene for pancreatic lipase resides on chromosome 19, while the gene for its cofactor, colipase, is on chromosome 17. A gene for a protein with sequence similarity to pancreatic lipase was tightly linked (no observed recombination) to the gene for pancreatic lipase, suggesting a gene cluster. The gene for hormone-sensitive lipase is near the gene cluster containing apolipoproteins C-II and E on chromosome 7. The gene for hepatic lipase is near the gene for apolipoprotein A-I on chromosome 9. The carboxyl ester lipase gene resides on chromosome 2. Previously, we have mapped the gene for lipoprotein lipase to chromosome 8. Thus, with the exception of pancreatic lipase and a related protein, these lipase genes, including several that are members of a gene family, are widely dispersed in the genome. Comparison of chromosomal locations for these genes in mouse and humans shows that the previously observed interspecies syntenies are preserved.
ESTHER : Warden_1993_J.Lipid.Res_34_1451
PubMedSearch : Warden_1993_J.Lipid.Res_34_1451
PubMedID: 8105016

Title : Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: analysis of a large pedigree from the Bogalusa Heart Study - Heiba_1993_Am.J.Med.Genet_47_875
Author(s) : Heiba IM , DeMeester CA , Xia YR , Diep A , George VT , Amos CI , Srinivasan SR , Berenson GS , Elston RC , Lusis AJ
Ref : American Journal of Medicine Genet , 47 :875 , 1993
Abstract : A pedigree of a large family with high prevalence of heart disease is subjected to association and sib-pair linkage analysis to investigate the role of 5 candidate genes in the regulation of lipoprotein metabolism and the development of coronary artery disease. At the 5% nominal significance level, the apolipoprotein B locus (APOB) was found to be linked to high-density lipoprotein cholesterol level (HDL-C), low-density lipoprotein cholesterol level (LDL-C), the ratio HDL-C/LDL-C, and apolipoprotein AI level times this ratio (apoAI x LDL-C/HDL-C). APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004). No significant linkage results were found with cholesterol ester transfer protein (CETP). At the 1% nominal significance level, CETP [TaqI(B)] showed significant association with LDL-C, apoB, and HDL-C/LDL-C. There was significant linkage of lipoprotein lipase (LPL) with very-low-density lipoprotein cholesterol and the ratio apoAI/HDL-C, and strong association results between LPL (HindIII) and triglyceride levels (P = 0.005). At the 5% nominal significance level, haptoglobin (HPA) was associated with HDL-C, HDL-C/LDL-C, apoAI/HDL-C and apoAI x LDL-C/HDL-C. The apolipoprotein AI locus did not show any significant linkages or associations. The study thus indicated that genetic variation of APOB, LPL, CETP, and lecithin cholesterol acyl transferase (which is linked to HPA and CETP) may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary artery disease.
ESTHER : Heiba_1993_Am.J.Med.Genet_47_875
PubMedSearch : Heiba_1993_Am.J.Med.Genet_47_875
PubMedID: 8279486

Title : Assignment of human pancreatic lipase gene (PNLIP) to chromosome 10q24-q26 - Davis_1991_Genomics_11_1164
Author(s) : Davis RC , Diep A , Hunziker W , Klisak I , Mohandas T , Schotz MC , Sparkes RS , Lusis AJ
Ref : Genomics , 11 :1164 , 1991
Abstract : Human pancreatic lipase (EC is a 56-kDa protein secreted by the acinar pancreas and is essential for the hydrolysis and absorption of long-chain triglyceride fatty acids in the intestine. In vivo, the 12-kDa protein cofactor, colipase, is required to anchor lipase to the surface of lipid micelles, counteracting the destabilizing influence of bile salts. Southern blot analysis, using a pancreatic lipase cDNA to probe DNA from mouse-human somatic cell hybrids, indicated that the pancreatic lipase gene (PNLIP) resides on human chromosome 10. In situ hybridization to human metaphase chromosomes confirmed the cell hybrid results and further localized the gene to the 10q24-qter region with the strongest peak at q26.1.
ESTHER : Davis_1991_Genomics_11_1164
PubMedSearch : Davis_1991_Genomics_11_1164
PubMedID: 1783385
Gene_locus related to this paper: human-PNLIP

Title : Carboxyl ester lipase: a highly polymorphic locus on human chromosome 9qter - Taylor_1991_Genomics_10_425
Author(s) : Taylor AK , Zambaux JL , Klisak I , Mohandas T , Sparkes RS , Schotz MC , Lusis AJ
Ref : Genomics , 10 :425 , 1991
Abstract : Carboxyl ester lipase (CEL) is a major component of pancreatic juice and is responsible for the hydrolysis of cholesterol esters as well as a variety of other dietary esters. As part of an effort to elucidate the role of this enzyme in the genetic control of lipid metabolism, we report here the chromosomal mapping of the gene for CEL to the most distal part of the long arm of human chromosome 9 using analysis of mouse-human somatic cell hybrids and in situ hybridization to chromosomes. A chromosome 9 translocation was utilized to determine the position of the CEL gene relative to various genetic markers previously localized to this region. Finally, we report that the CEL locus exhibits a high degree of polymorphism and contains a hypervariable region of the insertion/deletion variety.
ESTHER : Taylor_1991_Genomics_10_425
PubMedSearch : Taylor_1991_Genomics_10_425
PubMedID: 1676983
Gene_locus related to this paper: human-CEL

Title : DNA polymorphism haplotypes of the human lipoprotein lipase gene: possible association with high density lipoprotein levels - Heizmann_1991_Hum.Genet_86_578
Author(s) : Heizmann C , Kirchgessner T , Kwiterovich PO , Ladias JA , Derby C , Antonarakis SE , Lusis AJ
Ref : Hum Genet , 86 :578 , 1991
Abstract : Lipoprotein lipase (LPL) plays a central role in the metabolism of lipoproteins by hydrolyzing the core triglycerides of circulating very low density lipoproteins and chylomicrons. The enzyme is encoded by a gene about 30 kb in size located on the short arm of human chromosome 8. We have determined the locations of the four common DNA polymorphisms along the gene, including a polymorphism that occurred only among an American black population examined. These restriction site polymorphisms were used for haplotype analysis of Mediterranean and US black families. Estimation of the extent of nonrandom association between these polymorphisms indicated considerable linkage disequilibrium between these sites. No correlation was observed between the level of linkage disequilibrium and the physical distance of the polymorphic sites. The polymorphism information content of the haplotypes ranged from 0.65 to 0.74, thereby constituting a relatively useful genetic marker on chromosome 8. We tested for possible associations between the polymorphisms and circulating lipoprotein phenotypes in a population of 139 Caucasians undergoing coronary arteriography and 50 of their spouses. Some possibly significant associations between LPL gene polymorphisms and levels of high density lipoprotein cholesterol (P = 0.015) and total plasma cholesterol (P = 0.025) were observed. In contrast to a previous report, we found no significant associations with the levels of plasma triglycerides.
ESTHER : Heizmann_1991_Hum.Genet_86_578
PubMedSearch : Heizmann_1991_Hum.Genet_86_578
PubMedID: 1673959

Title : Tissue-specific expression, developmental regulation, and chromosomal mapping of the lecithin: cholesterol acyltransferase gene. Evidence for expression in brain and testes as well as liver - Warden_1989_J.Biol.Chem_264_21573
Author(s) : Warden CH , Langner CA , Gordon JI , Taylor BA , McLean JW , Lusis AJ
Ref : Journal of Biological Chemistry , 264 :21573 , 1989
Abstract : Lecithin:cholesterol acyltransferase (LCAT) catalyzes the esterification of cholesterol in high density lipoproteins, thereby facilitating transport of excess cholesterol from peripheral tissues to liver. We report here studies of the developmental, dietary, and genetic control of LCAT gene expression. In adult male Sprague-Dawley rats fed a standard chow diet LCAT mRNA was most abundant in liver, a major source of the plasma enzyme, but appreciable levels were also present in brain and testes. Since both brain and testes are isolated from blood by tight cellular barriers, undoubtedly greatly reducing the level of plasma-derived LCAT in cerebrospinal fluid and testes, the production of LCAT in these tissues may be important for removal of excess cholesterol. Noteworthy changes in the expression of LCAT mRNA were observed during development of both rodents and humans. On the other hand, LCAT mRNA levels were relatively resistant to dietary challenge or to drugs affecting cholesterol metabolism. Since human epidemiological studies have suggested an association between LCAT levels and variations of high density lipoprotein cholesterol, we examined LCAT gene polymorphisms in a mouse animal model. Mapping of the LCAT gene (Lcat) to mouse Chromosome 8 within 2 centimorgans of the Es-2 locus indicates that it does not correspond to any previously mapped loci affecting high density lipoprotein phenotypes in the mouse.
ESTHER : Warden_1989_J.Biol.Chem_264_21573
PubMedSearch : Warden_1989_J.Biol.Chem_264_21573
PubMedID: 2600083
Gene_locus related to this paper: mouse-lcat

Title : Genetic and developmental regulation of the lipoprotein lipase gene: loci both distal and proximal to the lipoprotein lipase structural gene control enzyme expression - Kirchgessner_1989_J.Biol.Chem_264_1473
Author(s) : Kirchgessner TG , LeBoeuf RC , Langner CA , Zollman S , Chang CH , Taylor BA , Schotz MC , Gordon JI , Lusis AJ
Ref : Journal of Biological Chemistry , 264 :1473 , 1989
Abstract : We report here a study of the developmental and genetic control of tissue-specific expression of lipoprotein lipase, the enzyme responsible for hydrolysis of triglycerides in chylomicrons and very low density lipoproteins. Lipoprotein lipase (LPL) mRNA is present in a wide variety of adult rat and mouse tissues examined, albeit at very different levels. A remarkable increase in the levels of LPL mRNA occurs in heart over a period of several weeks following birth, closely paralleling developmental changes in lipase activity and myocardial beta-oxidation capacity. Large increases in LPL mRNA also occur during differentiation of 3T3L1 cells to adipocytes. As previously reported, at least two separate genetic loci control the tissue-specific expression of LPL activity in mice. One of the loci, controlling LPL activity in heart, is associated with an alteration in LPL mRNA size, while the other, controlling LPL activity in adipose tissue, appears to affect the translation or post-translational expression of LPL. To examine whether these genetic variations are due to mutations of the LPL structural locus, we mapped the LPL gene to a region of mouse chromosome 8 using restriction fragment-length polymorphisms and analysis of hamster-mouse somatic cell hybrids. This region is homologous to the region of human chromosome 8 which contains the human LPL gene as judged by the conservation of linked genetic markers. Genetic variations affecting LPL expression in heart cosegregated with the LPL gene, while variations affecting LPL expression in adipose tissue did not. Furthermore, Southern blotting analysis indicates that LPL is encoded by a single gene and, thus, the genetic differences are not a consequence of independent regulation of two separate genes in the two tissues. These results suggest the existence of cis-acting elements for LPL gene expression that operate in heart but not adipose tissue. Our results also indicate that two genetic mutations resulting in deficiencies of LPL in mice, the W mutation on chromosome 5 and the cld mutation on mouse chromosome 17, do not involve the LPL structural gene locus. Finally, we show that the gene for hepatic lipase, a member of a gene family with LPL, is unlinked to the gene for LPL. This indicates that combined deficiencies of LPL and hepatic lipase, observed in humans as well as in certain mutant strains of mice, do not result from focal disruptions of a cluster of lipase genes.
ESTHER : Kirchgessner_1989_J.Biol.Chem_264_1473
PubMedSearch : Kirchgessner_1989_J.Biol.Chem_264_1473
PubMedID: 2563260
Gene_locus related to this paper: mouse-1hlip

Title : Two polymorphisms for the human hepatic lipase (HL) gene -
Author(s) : Heinzmann C , Ladias J , Antonarakis S , Diep A , Schotz M , Lusis AJ
Ref : Nucleic Acids Research , 16 :4739 , 1988
PubMedID: 2454457

Title : Nucleotide sequence of rat adipose hormone sensitive lipase cDNA -
Author(s) : Holm C , Kirchgessner TG , Svenson KL , Lusis AJ , Belfrage P , Schotz MC
Ref : Nucleic Acids Research , 16 :9879 , 1988
PubMedID: 3186461
Gene_locus related to this paper: ratno-hslip

Title : Human lipoprotein lipase complementary DNA sequence - Wion_1987_Science_235_1638
Author(s) : Wion KL , Kirchgessner TG , Lusis AJ , Schotz MC , Lawn RM
Ref : Science , 235 :1638 , 1987
Abstract : Lipoprotein lipase is a key enzyme of lipid metabolism that acts to hydrolyze triglycerides, providing free fatty acids for cells and affecting the maturation of circulating lipoproteins. It has been proposed that the enzyme plays a role in the development of obesity and atherosclerosis. The human enzyme has been difficult to purify and its protein sequence was heretofore undetermined. A complementary DNA for human lipoprotein lipase that codes for a mature protein of 448 amino acids has now been cloned and sequenced. Analysis of the sequence indicates that human lipoprotein lipase, hepatic lipase, and pancreatic lipase are members of a gene family. Two distinct species of lipoprotein lipase messenger RNA that arise from alternative sites of 3'-terminal polyadenylation were detected in several different tissues.
ESTHER : Wion_1987_Science_235_1638
PubMedSearch : Wion_1987_Science_235_1638
PubMedID: 3823907
Gene_locus related to this paper: human-LPL

Title : The sequence of cDNA encoding lipoprotein lipase. A member of a lipase gene family - Kirchgessner_1987_J.Biol.Chem_262_8463
Author(s) : Kirchgessner TG , Svenson KL , Lusis AJ , Schotz MC
Ref : Journal of Biological Chemistry , 262 :8463 , 1987
Abstract : cDNA clones corresponding to the entire coding region of mature lipoprotein lipase were identified by antibody screening of a mouse macrophage library and sequenced. The predicted amino acid sequence indicates that the mature protein contains 447 amino acids with a molecular weight of 50,314. Comparison of the nucleotide and amino acid sequence with those of rat hepatic lipase and porcine pancreatic lipase reveals extensive homology among the enzymes, indicating that they are members of a gene family of lipases. Most striking is a conservation of five disulfide bridges in all three enzymes, strongly suggesting that the enzymes have similar overall folding patterns. Lipoprotein lipase is also shown to be extraordinarily conserved among mouse, human, and bovine species. The mRNA for lipoprotein lipase is abundant in heart and adipose tissue but is also present in a wide variety of other tissues. There are two major species of mRNA in mouse and human tissues examined, 3.6 and 3.4 kilobases (kb) in size. Rat tissues, on the other hand, contain only the 3.6-kb species while bovine tissues contain an additional 1.7-kb species.
ESTHER : Kirchgessner_1987_J.Biol.Chem_262_8463
PubMedSearch : Kirchgessner_1987_J.Biol.Chem_262_8463
PubMedID: 3597382
Gene_locus related to this paper: mouse-lipli

Title : RFLP for the human lipoprotein lipase (LPL) gene: HindIII -
Author(s) : Heinzmann C , Ladias J , Antonarakis S , Kirchgessner T , Schotz M , Lusis AJ
Ref : Nucleic Acids Research , 15 :6763 , 1987
PubMedID: 2888089

Title : Human genes involved in lipolysis of plasma lipoproteins: mapping of loci for lipoprotein lipase to 8p22 and hepatic lipase to 15q21 - Sparkes_1987_Genomics_1_138
Author(s) : Sparkes RS , Zollman S , Klisak I , Kirchgessner TG , Komaromy MC , Mohandas T , Schotz MC , Lusis AJ
Ref : Genomics , 1 :138 , 1987
Abstract : We have used cDNA probes for lipoprotein lipase and hepatic lipase to determine the chromosomal and subchromosomal locations of the human genes for these lipolytic enzymes. Southern blot analysis of genomic DNA from 17 independent mouse-human somatic cell hybrids demonstrated the presence of the gene for human lipoprotein lipase on chromosome 8, whereas the gene for hepatic lipase was on chromosome 15. Regional mapping of the genes by in situ hybridization to human chromosomes indicated that the lipoprotein lipase gene (LPL) resides in the p22 region of chromosome 8, while hepatic lipase gene (HL) resides in the q21 region of chromosome 15. We previously reported, on the basis of nucleotide and amino acid homologies, that these genes are members of a gene family of lipases, and, thus, the present findings indicate that the members of this family are dispersed. The results are also of significance with respect to disorders involving deficiencies of the enzymes. In particular, they suggest that certain rare combined deficiencies of both enzymes do not involve mutations of the structural loci.
ESTHER : Sparkes_1987_Genomics_1_138
PubMedSearch : Sparkes_1987_Genomics_1_138
PubMedID: 3692485

Title : Preparation of microsomal beta-glucuronidase and its membrane anchor protein, egasyn -
Author(s) : Lusis AJ
Ref : Methods Enzymol , 96 :557 , 1983
PubMedID: 6656645
Gene_locus related to this paper: human-CES1

Title : Relationships between levels of membrane-bound glucuronidase and the associated protein egasyn in mouse tissues - Lusis_1977_J.Cell.Biol_73_728
Author(s) : Lusis AJ , Paigen K
Ref : Journal of Cell Biology , 73 :728 , 1977
Abstract : Mouse beta-glucuronidase has a dual intracellular localization, being present in both endoplasmic reticulum and lysosomes of several tissues. Previous studies demonstrated that the protein egasyn is complexed with microsomal but not lysosomal glucuronidase and that a mutant lacking egasyn is deficient in microsomal, but not lysosomal, glucuronidase. By means of a recently developed radioimmunoassay for egasyn, the relationship between microsomal glucuronidase levels and egasyn levels has been examined in various adult tissues, during postnatal development in liver, and after androgen induction of glucuronidase in kidney. The results indicate that the relative availability of egasyn determines the balance between glucuronidase incorporation into membranes and that into lysosomes.
ESTHER : Lusis_1977_J.Cell.Biol_73_728
PubMedSearch : Lusis_1977_J.Cell.Biol_73_728
PubMedID: 873997
Gene_locus related to this paper: human-CES1

Title : Inheritance in mice of the membrane anchor protein egasyn: the Eg locus determines egasyn levels - Lusis_1977_Biochem.Genet_15_115
Author(s) : Lusis AJ , Tomino S , Paigen K
Ref : Biochemical Genetics , 15 :115 , 1977
Abstract : Previous studies have suggested that the binding of mouse flucuronidase to endoplasmic reticulum membrane is stabilized by the membrane protein egasyn. Using a radioimmunoassay for egasyn, we have now examined the inheritance of egasyn levels in mice. Mice of the inbred strain C57BL/6J, which have normal levels of microsomal glucuronidase, contained 56 +/- 10 mug egasyn per gram of liver. Mice of the inbred strain YBR, which carry the Eg0 mutation resulting in the absence of microsomal glucuronidase, did not contain detectable levels of egasyn. The F1 progeny of these two strains contained intermediate levels of egasyn, 25 +/- 4 mug egasyn per gram of liver. Progeny from the backcross of these F1 animals to YBR were distributed equally into two discrete phenotypic classes. One class lacked both egasyn and microsomal glucuronidase, while the other class contained 25 +/- 3 mug egasyn per gram of liver and contained normal levels of microsomal glucuronidase. Thus egasyn levels are determined by the Eg locus and show additive inheritance. These results suggest that the Eg gene codes for egasyn and that it is the inability to produce egasyn that results in a deficiency of microsomal glucuronidase in the Eg0 mutant.
ESTHER : Lusis_1977_Biochem.Genet_15_115
PubMedSearch : Lusis_1977_Biochem.Genet_15_115
PubMedID: 849245
Gene_locus related to this paper: human-CES1

Title : Isolation, characterization, and radioimmunoassay of murine egasyn, a protein stabilizing glucuronidase membrane binding - Lusis_1976_J.Biol.Chem_251_7753
Author(s) : Lusis AJ , Tomino S , Paigen K
Ref : Journal of Biological Chemistry , 251 :7753 , 1976
Abstract : Glucuronidase present in lysosomes of mouse liver occurs as the free tetramer, whereas glucuronidase present in endoplasmic reticulum occurs in macromolecular complexes containing one to four molecules of the protein egasyn. Earlier genetic and biochemical studies suggest that these complexes, or M forms, function to stabilize the membrane binding of glucoronidase. The detergent Triton X-100 extracts glucuronidase-egasyn complexes intact and they dissociate in the presence of the detergent deoxycholate or upon heating. We have now purfied egasyn by releasing it from antiglucuronidase immunoprecipitates of M forms under relatively mild conditions, such as treatment with deoxycholate or heating at 50 degrees. Isolated egasyn is a glycoprotein of molecular weight about 64,000 and is not unusually hydrophobic in amino acid composition. Monospecific antibody to egasyn was raised. This antibody showed no cross-reactivity with purified beta-glucuronidase and antibody to glucuronidase failed to react with purified egasyn; however, both antibodies bound to egasyn-glucuronidase complexes. A procedure for the radioimmunoassay of egasyn was developed utilizing egasyn labeled with iodine 125. Most of the antigenic sites of egasyn in homogenates of normal liver are masked after extraction with Triton X-100 and only become immunoreactive after exposure to deoxycholate. After unmasking, mouse liver proved to contain about 56 mug of egasyn/g, nearly all of which is localized to the microsomal fraction. Of this total only about 10% was complexed with glucuronidase, suggesting theat the bulk of the egasyn present may be complexed with other proteins. Mice of the inbred strain YBR, which carry the EgO mutation resulting in the absence of microsomal glucuronidase, lacked immunoreactive egasyn, suggesting that the primary defect in this strain lies in the unavailabililty of agasyn to form complexes. There is now considerable evidence in support of the concept that the microsomal forms of glucuronidase exist in membranes complexed with egasyn and that formation of these complexes is required for maintenance of glucuronidase in membranes. Egasyn may represent one of a class of membrane anchor proteins that each stabilize the membrane binding of a charcteristic set of proteins.
ESTHER : Lusis_1976_J.Biol.Chem_251_7753
PubMedSearch : Lusis_1976_J.Biol.Chem_251_7753
PubMedID: 826534
Gene_locus related to this paper: human-CES1