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

doi:10.1073/pnas.0438039100

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

^*Section of Endocrinology and Metabolism, Departments of Medicine and Molecular and Cellular Biology, and ^†Section of Cardiology and Atherosclerosis, Department of Medicine, Baylor College of Medicine and Methodist Hospital, Houston, TX 77030; ^‡LipoScience, Raleigh, NC 27610; and ^§St. Luke's Episcopal Hospital, Houston, TX 77030

Communicated by Salih J. Wakil, Baylor College of Medicine, Houston, TX (received for review November 22, 2002)

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.

lipoprotein metabolism‖atherosclerosis‖gene targeting

Footnotes

↵ ¶ To whom correspondence should be addressed at: Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room N520.10, Houston, TX 77030. E-mail: lchan{at}bcm.tmc.edu.
Abbreviations:

EL,

endothelial lipase;

EL−/−,

homozygous EL knockout;

FCR,

fractional catabolic rate;

HDL,

high-density lipoprotein;

HDL-c,

HDL cholesterol;

HL,

hepatic lipase;

LDL,

low-density lipoprotein;

LPL,

lipoprotein lipase;

LCAS,

Lipoprotein and Coronary Atherosclerosis Study;

LCAT,

lecithin:cholesterol acyltransferase;

LIPG,

human EL gene;

PLTP,

phospholipid transfer protein;

SNP,

single-nucleotide polymorphism;

SR-BI,

scavenger receptor BI;

VLDL,

very low-density lipoprotein