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(Circulation Research. 2008;103:131.)
© 2008 American Heart Association, Inc.

Editorials

When HDL Gets Fat ...

Robert J. Brown, Daniel J. Rader

From the Department of Medicine and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Daniel J. Rader, 654 BRB II/III, University of Pennsylvania School of Medicine, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader@mail.med.upenn.edu

See related article, pages 159–166

Key Words: remnant HDL • hepatic lipase • endothelial lipase • reverse cholesterol transport • insulin resistance

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Because low levels of plasma high density lipoprotein cholesterol (HDL-C) are a major independent risk factor for atherosclerotic cardiovascular disease,¹ the mechanisms leading to low HDL-C are of substantial biological and clinical importance. Low HDL-C is most commonly seen in persons who have other components of the "metabolic syndrome," particularly increased waist circumference, elevated triglycerides (TG), and elevated fasting glucose, which along with low HDL-C are indicators of insulin resistance.² Kinetic studies in humans have indicated that the turnover of the major HDL protein apolipoprotein A-I (apoA-I) is increased in patients with the characteristics of metabolic syndrome and insulin resistance.^3,4 The mechanisms of hypercatabolism of HDL in this setting have been the subject of substantial investigation.

The insulin resistant state is associated with elevated plasma levels of TG-rich lipoproteins (TRL),⁵ derived from the liver and the intestine, as well as with elevated levels of the cholesteryl ester transfer protein (CETP),^6,7 which transfers TG from TRL to HDL in exchange for cholesteryl esters. Accelerated CETP-mediated lipid exchange siphons cholesterol out of and transfers TG into HDL, resulting in a cholesterol-depleted and TG-enriched HDL. Enrichment of HDL with TG makes it a much better substrate for hepatic lipase (HL), which is also clearly elevated in insulin resistant states.⁸ Lewis and colleagues have previously shown through a series of elegant studies in rabbits and humans that TG-enriched HDL is more rapidly catabolized than "native" HDL^9–11 and that this requires the action of HL on the TG-enriched HDL, with hydrolysis of the TG to . . . [Full Text of this Article]