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标题：Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response
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作者：Lu, Biao ; Moser, Arthur H. ; Shigenaga, Judy K. 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2006
卷号：47
期号：10
页码：2179-2190
DOI：10.1194/jlr.M500540-JLR200
出版社：American Society for Biochemistry and Molecular Biology
摘要：The acute-phase response (APR) leads to alterations in lipidmetabolism and type II nuclear hormone receptors, which regulatelipid metabolism, are suppressed, in liver, heart, and kidney.Here, we examine the effect of the APR in adipose tissue. Inmice, lipopolysaccharide produces a rapid, marked decrease inmRNA levels of nuclear hormone receptors [peroxisome proliferator-activatedreceptor ${gamma}$ (PPAR ${gamma}$ ), liver X receptor ${alpha}$ (LXR ${alpha}$ ) and LXRß,thyroid receptor ${alpha}$ (TR ${alpha}$ ) and TRß, and retinoid X receptor ${alpha}$ (RXR ${alpha}$ ) and RXRß] and receptor coactivators [cAMP responseelement binding protein, steroid receptor coactivator 1 (SRC1)and SRC2, thyroid hormone receptor-associated protein, and peroxisomeproliferator-activated receptor ${gamma}$ co-activator 1 ${alpha}$ (PGC1 ${alpha}$ ) 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. Weshow that key TG synthetic enzymes, 1-acyl-sn-glycerol-3-phosphateacyltransferase-2, monoacylglycerol acyltransferase 1, and diacylglycerolacyltransferase 1, are PPAR ${gamma}$ -regulated genes and that they alsodecrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor- ${alpha}$ (TNF- ${alpha}$ ) significantly decreases PPAR ${gamma}$ , LXR ${alpha}$ and LXRß,RXR ${alpha}$ and RXRß, SRC1 and SRC2, and PGC1 ${alpha}$ and PGC1ßmRNA levels, which are associated with a marked reduction inreceptor-regulated genes. Moreover, TNF- ${alpha}$ significantly reducesPPAR and LXR response element-driven transcription. Thus, theAPR suppresses the expression of many nuclear hormone receptorsand their coactivators in adipose tissue, which could be a mechanismto coordinately downregulate TG biosynthesis and thereby redirectlipids to other critical organs during the APR. Supplementary key words lipopolysaccharide • lipid metabolism • peroxisome proliferator-activated receptor ${gamma}$ • 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 ${gamma}$ 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