Journal of Lipid Research (Oct 2006)

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,
  • Carl Grunfeld

Journal volume & issue
Vol. 47, no. 10
pp. 2179 – 2190

Abstract

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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 γ (PPARγ), liver X receptor α (LXRα) and LXRβ, thyroid receptor α (TRα) and TRβ, and retinoid X receptor α (RXRα) and RXRβ] 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 γ co-activator 1α (PGC1α) and PGC1β] 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 PPARγ-regulated genes and that they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor-α (TNF-α) significantly decreases PPARγ, LXRα and LXRβ, RXRα and RXRβ, SRC1 and SRC2, and PGC1α and PGC1β mRNA levels, which are associated with a marked reduction in receptor-regulated genes. Moreover, TNF-α 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.

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