High-density lipoprotein hydrolysis by endothelial lipase activates PPARα -: A candidate mechanism for high-density lipoprotein-mediated repression of leukocyte adhesion

Although high-density lipoprotein (HDL) is known to inhibit endothelial adhesion molecule expression, the mechanism for this anti-inflammatory effect remains obscure. Surprisingly, we observed that HDL no longer decreased adhesion of U937 monocytoid cells to tumor necrosis factor (TNF)alpha-stimulated human endothelial cells (EC) in the presence of the general lipase inhibitor tetrahydrolipstatin. In considering endothelial mechanisms responsible for this effect, we found that endothelial lipase (EL) overexpression in both EC and non-EL-expressing NIH/3T3 mouse embryonic fibroblasts cells significantly decreased TNF alpha-induced VCAM1 expression and promoter activity in a manner dependent on HDL concentration and intact EL activity. Given recent evidence for lipolytic activation of peroxisome proliferator-activated receptors (PPARs) - nuclear receptors implicated in metabolism, atherosclerosis, and inflammation - we hypothesized HDL hydrolysis by EL is an endogenous endothelial mechanism for PPAR activation. In both EL-transfected NIH cells and bovine EC, HDL significantly increased PPAR ligand binding domain activation in the order PPAR-alpha >> -gamma > -delta. Moreover, HDL stimulation induced expression of the canonical PPAR alpha-target gene acyl-CoA-oxidase (ACO) in a PPAR alpha-dependent manner in ECs. Conditioned media from EL-adenovirus transfected cells but not control media exposed to HDL also activated PPAR alpha. PPAR alpha activation by EL was most potent with HDL as a substrate, with lesser effects on LDL and VLDL. Finally, HDL inhibited leukocyte adhesion to TNF alpha-stimulated ECs isolated from wild-type but not PPAR alpha-deficient mice. This data establishes HDL hydrolysis by EL as a novel, distinct natural pathway for PPAR alpha activation and identifies a potential mechanism for HDL-mediated repression of VCAM1 expression, with significant implications for both EL and PPARs in inflammation and vascular biology.