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J. Biol. Chem., Vol. 279, Issue 46, 47626-47632, November 12, 2004

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Divergent Effects of Peroxisome Proliferator-activated Receptor Agonists and Tumor Necrosis Factor on Adipocyte ApoE Expression^*

Lili Yue, Neda Rasouli, Gouri Ranganathan, Philip A. Kern, and Theodore Mazzone¶

From the Department of Medicine, University of Illinois, Chicago, Illinois 60612 and Central Arkansas Veterans Healthcare System and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

ApoE is expressed in multiple mammalian cell types in which it supports cellular differentiated function. In this report we demonstrate that apoE expression in adipocytes is regulated by factors involved in modulating systemic insulin sensitivity. Systemic treatment with pioglitazone increased systemic insulin sensitivity and increased apoE mRNA levels in adipose tissue by 2–3-fold. Treatment of cultured 3T3-L1 adipocytes with ciglitazone increased apoE mRNA levels by 2–4-fold in a dose-dependent manner and increased apoE secretion from cells. Conversely, treatment of adipocytes with tumor necrosis factor (TNF) reduced apoE mRNA levels and apoE secretion by 60%. Neither insulin nor a peroxisome proliferator-activated receptor (PPAR) agonist regulated adipocyte apoE gene expression. In addition, treatment of human monocyte-derived macrophages with ciglitazone did not regulate expression of apoE. Additional analyses using reporter genes indicated that the effect of TNF and PPAR agonists on the apoE gene was mediated via distinct gene control elements. The TNF effect was mediated by elements within the proximal promoter, whereas the PPAR effect was mediated by elements within a downstream enhancer. However, the addition of TNF substantially reduced the absolute levels of apoE reporter gene response even in the presence of ciglitazone. These results indicate for the first time that adipose tissue expression of apoE is modulated by physiologic regulators of insulin sensitivity.

Received for publication, July 26, 2004 , and in revised form, August 25, 2004.

^* This work was supported by National Institutes of Health Grant HL 39653 (to T. M.), a Merit Review Grant from the Veterans Administration, a grant from the American Diabetes Association, an investigator-initiated grant from Takeda Pharmaceuticals, General Clinical Research Center Grant M01RR14288, and National Institutes of Health Grant DK 39176 (to P. A. K.). 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: Dept. of Medicine, University of Illinois, 1819 W. Polk St., M/C 797, Chicago, IL 60612. Tel.: 312-996-7989; Fax: 312-413-0437; E-mail: tmazzone{at}uic.edu.

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