Natarajan P

References (5)

Title : Human CIDEC transgene improves lipid metabolism and protects against high-fat diet-induced glucose intolerance in mice - Gupta_2022_J.Biol.Chem__
Author(s) : Gupta A , Balakrishnan B , Karki S , Slayton M , Jash S , Banerjee S , Grahn THM , Jambunathan S , Disney S , Hussein H , Kong D , Lowell BB , Natarajan P , Reddy UK , Gokce N , Sharma VM , Puri V
Ref : Journal of Biological Chemistry , :102347 , 2022
Abstract : Cell death-inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet (HFD)-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in HFD-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid-metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential 'drug' or a 'druggable' target to reverse obesity-induced lipotoxicity and glucose intolerance.
ESTHER : Gupta_2022_J.Biol.Chem__
PubMedSearch : Gupta_2022_J.Biol.Chem__
PubMedID: 35963433
Gene_locus related to this paper: human-ABHD5

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 : Myasthenia Gravis and COVID-19 - A Clinical Checkmate - Sivapurapu_2021_Anesth.Essays.Res_15_457
Author(s) : Sivapurapu V , Natarajan P , Bhat RR , Remadevi R
Ref : Anesth Essays Res , 15 :457 , 2021
Abstract : Myasthenia gravis (MG) patients with coronavirus disease (COVID-19) pose a unique challenge for intensive care management. Higher risk of infection is observed in patients with MG due to the immunosuppressant medications they are prescribed. The underlying component of respiratory muscle weakness predisposes these patients to experience a more severe form of illness. In the case of diagnosis of COVID-19 in MG patients, judicious continuation of immunosuppressants, avoiding drugs that worsen MG along with the continuation of cholinesterase inhibitors is prudent. Early diagnosis in cases with high-index of suspicion, extra precautions, COVID-appropriate behavior, and early immunization is paramount for the health of MG patients during this pandemic.
ESTHER : Sivapurapu_2021_Anesth.Essays.Res_15_457
PubMedSearch : Sivapurapu_2021_Anesth.Essays.Res_15_457
PubMedID: 35422544

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 : 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