Khetarpal SA

References (3)

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 : 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 : 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