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Journal of Lipid Research, Vol. 47, 2179-2190, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response

Biao Lu, Arthur H. Moser, Judy K. Shigenaga, Kenneth R. Feingold and Carl Grunfeld¹

Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121

Published, JLR Papers in Press, July 17, 2006.

¹ To whom correspondence should be addressed. e-mail: grunfld{at}ucsf.edu

The acute-phase response (APR) leads to alterations in lipid metabolism and type II nuclear hormone receptors, which regulate lipid metabolism, are suppressed, in liver, heart, and kidney. Here, we examine the effect of the APR in adipose tissue. In mice, lipopolysaccharide produces a rapid, marked decrease in mRNA levels of nuclear hormone receptors [peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR) and LXRß, thyroid receptor (TR) and TRß, and retinoid X receptor (RXR) and RXRß] and receptor coactivators [cAMP response element binding protein, steroid receptor coactivator 1 (SRC1) and SRC2, thyroid hormone receptor-associated protein, and peroxisome proliferator-activated receptor co-activator 1 (PGC1) and PGC1ß] along with decreased expression of target genes (adipocyte P2, phosphoenolpyruvate carboxykinase, glycerol-3-phosphate acyltransferase, ABCA1, apolipoprotein E, sterol-regulatory element binding protein-1c, glucose transport protein 4 (GLUT4), malic enzyme, and Spot14) involved in triglyceride (TG) and carbohydrate metabolism. We show that key TG synthetic enzymes, 1-acyl-sn-glycerol-3-phosphate acyltransferase-2, monoacylglycerol acyltransferase 1, and diacylglycerol acyltransferase 1, are PPAR-regulated genes and that they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor- (TNF-) significantly decreases PPAR, LXR and LXRß, RXR and RXRß, SRC1 and SRC2, and PGC1 and PGC1ß mRNA levels, which are associated with a marked reduction in receptor-regulated genes. Moreover, TNF- significantly reduces PPAR and LXR response element-driven transcription. Thus, the APR suppresses the expression of many nuclear hormone receptors and their coactivators in adipose tissue, which could be a mechanism to coordinately downregulate TG biosynthesis and thereby redirect lipids to other critical organs during the APR.

Supplementary key words lipopolysaccharide • lipid metabolism • peroxisome proliferator-activated receptor • cytokines

Abbreviations: AGPAT, 1-acyl-sn-glycerol-3-phosphate acyltransferase; aP2, adipocyte P2; apoE, apolipoprotein E; APR, acute-phase response; DGAT, diacylglycerol acyltransferase; GLUT4, glucose transport protein 4; GPAT, glycerol-3-phosphate acyltransferase; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; IL, interleukin; LPS, lipopolysaccharide; LXR, liver X receptor; LXRE, liver X receptor response element; ME, malic enzyme; MGAT, monoacylglycerol acyltransferase; PEPCK, phosphoenolpyruvate carboxykinase; PGC, peroxisome proliferator-activated receptor co-activator 1; PPAR, peroxisome proliferator-activated receptor; PPARE, peroxisome proliferator-activated receptor response element; RXR, retinoid X receptor; SRC, steroid receptor coactivator; SREBP, sterol-regulatory element binding protein; TG, triglyceride; TLR, Toll-like receptor; TNF, tumor necrosis factor; TR, thyroid receptor

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