Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure and metabolism

Ke Ma, Mehmet Cilingiroglu, James D. Otvos, Christie M. Ballantyne, Ali J. Marian, Lawrence Chan

Research output: Contribution to journalArticle

190 Scopus citations

Abstract

High-density lipoprotein (HDL) protects against atherosclerosis. Endothelial lipase (EL) has been postulated to be involved in lipoprotein, and possibly HDL, metabolism, yet the evidence has been scarce and conflicting. We have inactivated EL in mice by gene targeting. EL-/- mice have elevated plasma and HDL cholesterol, and increased apolipoproteins A-I and E. NMR analysis reveals an abundance of large HDL particles. There is down-regulation of the transcripts for phospholipid transfer protein, but up-regulation of those for hepatic lipase and lipoprotein lipase. Plasma lecithin:cholesterol acyltransferase is unchanged despite an increase in hepatic mRNA; lecithin:cholesterol acyltransferase activity toward endogenous EL-/- substrate is, however, reduced by 50%. HDL clearance is decreased in EL-/- mice; both the structure of HDL and the presence of EL are factors that determine the rate of clearance. To determine EL's role in humans, we find a significant association between a single-nucleotide polymorphism 584C/T in the EL (LIPG) gene and HDL cholesterol in a well characterized population of 372 individuals. We conclude that EL is a major determinant of HDL concentration, structure, and metabolism in mice, and a major determinant of HDL concentration in humans.

Original languageEnglish (US)
Pages (from-to)2748-2753
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number5
DOIs
StatePublished - Mar 4 2003

Keywords

  • Atherosclerosis
  • Gene targeting
  • Lipoprotein metabolism

ASJC Scopus subject areas

  • Genetics
  • General

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