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J. Biol. Chem., Vol. 278, Issue 41, 39874-39881, October 10, 2003
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Dual Roles for Lipolysis and Oxidation in Peroxisome Proliferation-Activator Receptor Responses to Electronegative Low Density Lipoprotein*
**
From the
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachussetts 02115, the Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089, ¶Sigma-Aldrich, St. Louis, Missouri 63103, and ||Merck Research Laboratories, Rahway, New Jersey 07065
Low density lipoprotein (LDL) exists in various forms that possess unique characteristics, including particle content and metabolism. One circulating subfraction, electronegative LDL (LDL(–)), which is increased in familial hypercholesterolemia and diabetes, is implicated in accelerated atherosclerosis. Cellular responses to LDL(–) remain poorly described. Here we demonstrate that LDL(–) increases tumor necrosis factor 
(TNF)–induced inflammatory responses through NF
B and AP-1 activation with corresponding increases in vascular cell adhesion molecule-1 (VCAM1) expression. LDL receptor overexpression increased these effects. In contrast, exposing LDL(–) to the key lipolytic enzyme lipoprotein lipase (LPL) reversed these responses, inhibiting VCAM1 below levels seen with TNF alone. LPL is known to act on lipoproteins to generate endogenous peroxisomal proliferator-activated receptor (PPAR) ligand, thus limiting inflammation. These responses varied according to the lipoprotein substrate triglyceride content (very low density lipoprotein >> LDL > high density lipoprotein). The PPAR activation seen with LDL, however, was disproportionately high. We show here that MUT LDL activates PPAR to an extent proportional to its LDL(–) content. As compared with LDL(–) alone, LPL-treated LDL(–) increased PPAR activation 20-fold in either cell-based transfection or radioligand displacement assays. LPL-treated LDL(–) suppressed NFB and AP-1 activation, increasing expression of the PPAR target gene IB, although only in the genetic presence of PPAR and with intact LPL hydrolysis. Mass spectrometry reveals that LPL-treatment of either LDL or LDL(–) releases hydroxy-octadecadienoic acids (HODEs), potent PPAR activators. These findings suggest LPL-mediated PPAR activation as an alternative catabolic pathway that may limit inflammatory responses to LDL(–).
Received for publication, June 25, 2003 , and in revised form, July 18, 2003.
* This work was supported in part by grants from the American Diabetes Association and the LeDucq Foundation (to J. P. and O. Z.) and National Institutes of Health Grant HL50350 (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Brigham and Women's Hospital, 77 Av. Louis Pasteur, NRB 740, Boston, MA 02115. Tel.: 617-525-4361; Fax: 617-525-4380; E-mail: jplutzky{at}rics.bwh.harvard.edu.
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