Abstract
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 gamma (PPARgamma), liver X receptor alpha (LXRalpha) and LXRbeta, thyroid receptor alpha (TRalpha) and TRbeta, and retinoid X receptor alpha (RXRalpha) and RXRbeta] 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 gamma co-activator 1alpha (PGC1alpha) and PGC1beta] 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 PPARgamma-regulated genes and that they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor-alpha (TNF-alpha) significantly decreases PPARgamma, LXRalpha and LXRbeta, RXRalpha and RXRbeta, SRC1 and SRC2, and PGC1alpha and PGC1beta mRNA levels, which are associated with a marked reduction in receptor-regulated genes. Moreover, TNF-alpha 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.
Highlights
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
An increase in adipose tissue lipolysis leads to increased circulating FFA levels, which provide a source of fatty acids for the increase in hepatic TG synthesis during the APR [3]
The increased lipolysis in adipose tissue is thought to be secondary to the Abbreviations: AGPAT, 1-acyl-sn-glycerol-3-phosphate acyltransferase; aP2, adipocyte P2; Apolipoprotein E (apoE), apolipoprotein E; APR, acute-phase response; DGAT, diacylglycerol acyltransferase; GLUT4, glucose transport protein 4; GPAT, glycerol-3-phosphate acyltransferase; 11b-HSD, 11b-hydroxysteroid dehydrogenase; IL, interleukin; LPS, lipopolysaccharide; LXR, liver X receptor; LXRE, liver X receptor response element; ME, malic enzyme; MGAT, monoacylglycerol acyltransferase; Phosphoenolpyruvate carboxykinase (PEPCK), phosphoenolpyruvate carboxykinase; PGC, peroxisome proliferator-activated receptor g co-activator 1; PPAR, peroxisome proliferatoractivated 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
Summary
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. The increased lipolysis in adipose tissue is thought to be secondary to the 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; 11b-HSD, 11b-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 g co-activator 1; PPAR, peroxisome proliferatoractivated 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. We demonstrate that LPS and zymosan, two different inducers of the APR, suppress the expression of several key type II nuclear hormone receptors and their coactivators, which play key roles in regulating lipid metabolism in adipose tissue. We show that the TG-synthesizing enzymes 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 (AGPAT2), monoacylglycerol acyltransferase 1 (MGAT1), and diacylglycerol acyltransferase 1 (DGAT1) are regulated by PPARg in a manner similar to glycerol-3-phosphate acyltransferase (GPAT) and that all are suppressed in the APR
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