A novel endothelial-derived lipase that modulates HDL metabolism

Abstract

High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease1. At least 50% of the variation in HDL cholesterol levels is genetically determined2,3, but the genes responsible for variation in HDL levels have not been fully elucidated. Lipoprotein lipase (LPL) and hepatic lipase (HL), two members of the triacylglyerol (TG) lipase family, both influence HDL metabolism2,4,5,6 and the HL (LIPC) locus has been associated with variation in HDL cholesterol levels in humans7,8. We describe here the cloning and in vivo functional analysis of a new member of the TG lipase family. In contrast to other family members, this new lipase is synthesized by endothelial cells in vitro and thus has been termed endothelial lipase (encoded by the LIPG gene). EL is expressed in vivo in organs including liver, lung, kidney and placenta, but not in skeletal muscle. In contrast to LPL and HL, EL has a lid of only 19 residues. EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-I. The endothelial expression, enzymatic profile and in vivo effects of EL suggest that it may have a role in lipoprotein metabolism and vascular biology.

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Figure 1: Human TG lipase family.
Figure 2: Expression of human EL.
Figure 3: Expression of EL in mice reduced HDL cholesterol and apoA-I levels.
Figure 4: Injection of AdhEL in LDL receptor-deficient mice reduced HDL cholesterol levels (a) to a greater extent than VLDL/LDL cholesterol levels ( b).

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Acknowledgements

We thank B. Tocque, A. Minnich and J. Glick for helpful discussions and S. French, J. Bruno, R. Howk, M. McCoy, P. Smith, A. Lillethun and R. Hughes for technical assistance.

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Correspondence to Daniel J. Rader.

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