Plasma levels of high-density lipoprotein (HDL) cholesterol are inversely associated with risk of atherosclerotic cardiovascular disease in humans, but recently the field has shifted from a focus on HDL-C concentrations to HDL function. HDL is believed to protect against atherosclerosis by promoting """"""""reverse cholesterol transport"""""""", as well as potentially through a variety of other protective properties. However, despite advances over the last decade, the molecular regulation of HDL metabolism and reverse cholesterol transport (RCT) remain incompletely understood, the relevance of other HDL properties remains uncertain, and the concept of directly targeting HDL therapeutically in humans remains unproven. Genome-wide association studies (GWAS) have established that all three members of the subfamily of extracellular lipases that act on lipoproteins, lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL), are significantly associated with variation in lipid traits including HDL-C levels. Furthermore, it is becoming clear that these lipases are finely regulated by a series of other proteins such as CETP, PLTP, ANGPTL3 and ANGPTL4. In fact, both common and low frequency genetic variants in all of the above genes have been shown to have highly significant associations with plasma TG and/or HDL-C levels, and in some cases with CAD. Our investigations into the roles of EL, HL and LPL, and their interactions with other proteins in modulating triglyceride and HDL metabolism, reverse cholesterol transport, and atherosclerosis span biochemical, cell biology, mouse and human translational studies in addressing the relevant questions. This subfamily of lipases is a potential target for novel therapeutic development, and these studies will provide greater understanding of their effects on HDL metabolism and function, enabling future treatments to prevent atherosclerosis.

Public Health Relevance

The goal of this project is to provide important new insight into the role of lipid-degrading enzymes (lipases) and their interactions with other proteins in modulating triglyceride (fat) and HDL (good) cholesterol metabolism in the development of atherosclerosis, as well as their human genetics as it relates to effects on HDL and coronary artery disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Liu, Lijuan
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Khetarpal, Sumeet A; Babb, Paul L; Zhao, Wei et al. (2018) Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of High-Density Lipoprotein Cholesterol in Humans. Circ Genom Precis Med 11:e002070
Xu, Yu-Xin; Redon, Valeska; Yu, Haojie et al. (2018) Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol. Atherosclerosis 268:196-206
Kuwano, Takashi; Bi, Xin; Cipollari, Eleonora et al. (2017) Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport. J Lipid Res 58:731-741
Khetarpal, Sumeet A; Zeng, Xuemei; Millar, John S et al. (2017) A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat Med 23:1086-1094
Qamar, Arman; Khetarpal, Sumeet A; Khera, Amit V et al. (2015) Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol 35:1880-8
Khetarpal, Sumeet A; Rader, Daniel J (2015) Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics. Arterioscler Thromb Vasc Biol 35:e3-9
Mehta, Nidhi; Qamar, Arman; Qu, Liming et al. (2014) Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. Arterioscler Thromb Vasc Biol 34:1057-63
Yang, Yanbo; Kuwano, Takashi; Lagor, William R et al. (2014) Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species. Lipids 49:505-15
Miksztowicz, VerĂ³nica; Schreier, Laura; McCoy, Mary et al. (2014) Role of SN1 lipases on plasma lipids in metabolic syndrome and obesity. Arterioscler Thromb Vasc Biol 34:669-75
Miksztowicz, Veronica; McCoy, Mary G; Schreier, Laura et al. (2012) Endothelial lipase activity predicts high-density lipoprotein catabolism in hemodialysis: novel phospholipase assay in postheparin human plasma. Arterioscler Thromb Vasc Biol 32:3033-40

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