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A more recent version of this article appeared on October 1, 2006

Papers In Press, published online ahead of print July 17, 2006
J. Lipid Res., doi:10.1194/jlr.M500540-JLR200
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Submitted on December 14, 2005
Revised on July 13, 2006
Accepted on July 17, 2006

Repression of type II nuclear hormone receptors, receptor coactivators, and their target genes in adipose tissues during the acute-phase response

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

Dermatology and Medicine Services, Veterans Administration Medical Center and University of California School of Medicine, San Francisco, San Francisco, CA 94121

Corresponding Author: frankbiao2000{at}yahoo.com

Infection and inflammation induce the acute-phase response, which leads to substantial alterations in lipid metabolism. Recent evidence suggests that type II nuclear hormone receptors, which play a key role in regulating lipid metabolism, are suppressed in liver, heart, and kidney during the APR. Therefore we examined the expression of type II nuclear hormone receptors and their coactivator as well as their target genes in adipose tissue from mice treated with lipopolysachoride (LPS) and in cultured 3T3-L1 adipocytes. LPS administration produces a rapid, marked decrease in mRNA levels of the type II nuclear hormone receptors (PPAR, LXRa and ß, TRa and ß, and RXRa and ß) as well as receptor coactivators (CBP, SRC1, SRC2, TRAP, and PGC1a and 1ß) in adipose tissue. This suppression is associated with the reduced expression of many known receptor regulated proteins (aP2, PEPCK, GPAT, ABCA1, ApoE, SREBP-1c, GLUT4, ME, and Spot 14), which are involved in triglyceride and carbohydrate metabolism. We show that key TG synthetic enzymes, AGPAT2, MGAT1, and DGAT1, are PPAR-regulated genes and they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor (TNFa) significantly decreases PPAR, LXRa and ß, RXR and , SRC1and 2, and PGC1a and ß mRNA levels. This decrease is also accompanied by a marked reduction in receptor-regulated genes. Moreover, TNFa significantly reduced PPAR and LXR response element-driven transcription as measured by PPRE- and LXRE-linked luciferase activity. We conclude that the APR suppresses the expression of many type II nuclear hormone receptors and their co-activators in adipose tissue, which could be a mechanism to coordinately downregulate triglyceride biosynthesis and thereby redirect lipid fuel to other critical organs during the APR.


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