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Am J Physiol Gastrointest Liver Physiol 282: G586-G597, 2002. First published December 12, 2001; doi:10.1152/ajpgi.00305.2001
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Vol. 282, Issue 4, G586-G597, April 2002

85-kDa cPLA2 plays a critical role in PPAR-mediated gene transcription in human hepatoma cells

Chang Han1, A. Jake Demetris1, George Michalopoulos1, James H. Shelhamer2, and Tong Wu1

1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; and 2 Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892

In an effort to understand the role of key eicosanoid-forming enzymes in the activation of peroxisome proliferator-activated receptor (PPAR), this study was designed to evaluate the possible contributions of cytosolic phospholipase A2 (cPLA2) and group IIA secretory phospholipase A2 (sPLA2) in the regulation of PPAR-mediated gene transcription in a human hepatoma cell line (HepG2). The HepG2 cells express both PPAR-alpha and -gamma but not PPAR-beta . Overexpression of cPLA2, but not group IIA sPLA2 in the HepG2 cells, caused a significantly increased PPAR-alpha /gamma -mediated reporter activity. Antisense inhibition of cPLA2 resulted in a significantly decreased PPAR-alpha /gamma activity. The PPAR-alpha /gamma -induced gene transcription in the HepG2 cells was inhibited by the cPLA2 inhibitors methyl arachidonyl fluorophosphonate and arachidonyltrifluoromethyl ketone, but not by the sPLA2 inhibitor LY311727. The expression of PPAR-alpha -mediated endogenous gene apolipoprotein A-II was increased in cells with overexpression of cPLA2, decreased in cells with antisense inhibition of cPLA2, but unaltered in cells with overexpression of group IIA sPLA2. The above results demonstrated an important role of cPLA2, but not group IIA sPLA2 in the control of PPAR activation. The cPLA2-mediated PPAR activation was likely mediated by arachidonic acid and prostaglandin E2. This study reveals a novel intracellular function of cPLA2 in PPAR activation in HepG2 cells. The cPLA2 thus may represent a potential therapeutic target for the control of PPAR-related liver and metabolic disorders such as obesity, lipid metabolic disorders, diabetes mellitus, and atherosclerosis.

HepG2 cell; liver; arachidonic acid; prostaglandin; peroxisome proliferator response element


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