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(Circulation Research. 2004;94:1554.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Endothelial Lipase Promotes the Catabolism of ApoB-Containing Lipoproteins

Uli C. Broedl, Cyrille Maugeais, John S. Millar, Weijun Jin, Ryan E. Moore, Ilia V. Fuki, Dawn Marchadier, Jane M. Glick, Daniel J. Rader

From the University of Pennsylvania, Philadelphia, Pa.

Correspondence to Daniel J. Rader, MD, University of Pennsylvania Medical Center, 654 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104-6160. E-mail rader{at}mail.med.upenn.edu

Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are "HDL animals" and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor–deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (EL^S149A); unexpectedly, expression of EL^S149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive EL^S149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.

Key Words: lipase • lipids • lipoproteins

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