Type Ii Nuclear Hormone Receptors, Coactivator, and Target Gene Repression in Adipose Tissue in the Acute-phase Response

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 g (PPARg), liver X receptor a (LXRa) and LXRb, thyroid receptor a (TRa) and TRb, and retinoid X receptor a (RXRa) and RXRb] 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 g co-activator 1a (PGC1a) and PGC1b] along with decreased expression of target genes (adipocyte P2, phos-phoenolpyruvate carboxykinase, glycerol-3-phosphate acyl-transferase, ABCA1, apolipoprotein E, sterol-regulatory element binding protein-1c, glucose transport protein 4 (GLUT4), malic enzyme, and Spot14) involved in triglycer-ide (TG) and carbohydrate metabolism. We show that key TG synthetic enzymes, 1-acyl-sn-glycerol-3-phosphate acyl-transferase-2, monoacylglycerol acyltransferase 1, and diacyl-glycerol acyltransferase 1, are PPARg-regulated genes and that they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor-a (TNF-a) significantly decreases PPARg, LXRa and LXRb, RXRa and RXRb, SRC1 and SRC2, and PGC1a and PGC1b mRNA levels, which are associated with a marked reduction in receptor-regulated genes. Moreover, TNF-a 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 biosyn-thesis and thereby redirect lipids to other critical organs during the APR. Type II nuclear hormone receptors , coactivator, and target gene repression in adipose tissue in the acute-phase response. The acute-phase response (APR) refers to an array of biochemical and metabolic changes that are induced by injurious stimuli, including infection and inflammation, trauma, burns, ischemic necrosis, and malignant tumors (1, 2). More recently, it has become widely appreciated that atherosclerosis, obesity, the metabolic syndrome, and diabetes are inflammatory disorders that also induce the APR (3–6). An early and consistent metabolic alteration during the APR is increased plasma FFA and triglyceride (TG) levels, characterized by an increase in VLDL (1, 3). These metabolic changes are thought to be beneficial to the host in the short term in fighting against invading pathogens and in repairing inflamed tissues after injury (1, 7). However, if prolonged, these changes in lipid and lipoprotein metabolism might contribute to dyslipidemia and atherogenesis (3, 8, …

[1]  K. Feingold,et al.  Downregulation of liver X receptor-alpha in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines. , 2005, Journal of lipid research.

[2]  K. Feingold,et al.  Suppression of estrogen-related receptor alpha and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response. , 2005, Journal of lipid research.

[3]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[4]  Frank Eisenhaber,et al.  Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase , 2004, Science.

[5]  Kenneth R Feingold,et al.  Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. , 2004, Journal of lipid research.

[6]  K. Feingold,et al.  Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. , 2004, American journal of physiology. Endocrinology and metabolism.

[7]  S. Souza,et al.  Lipase-selective Functional Domains of Perilipin A Differentially Regulate Constitutive and Protein Kinase A-stimulated Lipolysis* , 2003, Journal of Biological Chemistry.

[8]  A. Kimmel,et al.  Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation , 2003, The Journal of cell biology.

[9]  M. Lathrop,et al.  Prevalence of mutations in AGPAT2 among human lipodystrophies. , 2003, Diabetes.

[10]  K. Feingold,et al.  Repression of Farnesoid X Receptor during the Acute Phase Response* , 2003, The Journal of Biological Chemistry.

[11]  L. E. Hammond,et al.  Mitochondrial Glycerol-3-Phosphate Acyltransferase-Deficient Mice Have Reduced Weight and Liver Triacylglycerol Content and Altered Glycerolipid Fatty Acid Composition , 2002, Molecular and Cellular Biology.

[12]  V. Manganiello,et al.  Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. , 2002, Diabetes.

[13]  James L. Young,et al.  Cytokines in the Pathogenesis of Atherosclerosis , 2002, Thrombosis and Haemostasis.

[14]  J. Nadler,et al.  Role of inflammatory pathways in the development and cardiovascular complications of type 2 diabetes , 2002, Current diabetes reports.

[15]  R. Roth,et al.  Stimulation of Lipolysis and Hormone-sensitive Lipase via the Extracellular Signal-regulated Kinase Pathway* , 2001, The Journal of Biological Chemistry.

[16]  R. Evans,et al.  Nuclear receptors and lipid physiology: opening the X-files. , 2001, Science.

[17]  Robert V Farese,et al.  Cloning of DGAT2, a Second Mammalian Diacylglycerol Acyltransferase, and Related Family Members* , 2001, The Journal of Biological Chemistry.

[18]  M. Lisanti,et al.  The Lipopolysaccharide-activated Toll-like Receptor (TLR)-4 Induces Synthesis of the Closely Related Receptor TLR-2 in Adipocytes* , 2000, The Journal of Biological Chemistry.

[19]  K. Feingold,et al.  The Acute Phase Response Is Associated with Retinoid X Receptor Repression in Rodent Liver* , 2000, The Journal of Biological Chemistry.

[20]  Robert V Farese,et al.  Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat , 2000, Nature Genetics.

[21]  S. Humphries,et al.  Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? , 2000, Atherosclerosis.

[22]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[23]  Robert V Farese,et al.  Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  K. Feingold,et al.  In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines. , 1998, American journal of physiology. Endocrinology and metabolism.

[25]  Kenneth R Feingold,et al.  Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines. , 1998, American journal of physiology. Endocrinology and metabolism.

[26]  K. Feingold,et al.  Effects of endotoxin on lipid metabolism. , 1995, Biochemical Society transactions.

[27]  A. Bradley,et al.  Impaired energy homeostasis in C/EBP alpha knockout mice , 1995, Science.

[28]  G. Fantuzzi,et al.  Defective inflammatory response in interleukin 6-deficient mice , 1994, The Journal of experimental medicine.

[29]  K. Feingold,et al.  Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms. , 1994, Cytokine.

[30]  K. Feingold,et al.  Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance. , 1992, Journal of lipid research.

[31]  K. Feingold,et al.  In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis. , 1992, Endocrinology.

[32]  K. Feingold,et al.  Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis. , 1992, The American journal of physiology.

[33]  K. Feingold,et al.  Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. , 1992, The Journal of clinical endocrinology and metabolism.

[34]  M. Taskinen,et al.  Changes in serum lipoprotein pattern induced by acute infections. , 1988, Metabolism: clinical and experimental.

[35]  J. Paulauskis,et al.  Cloning and expression of mouse fatty acid synthase and other specific mRNAs. Developmental and hormonal regulation in 3T3-L1 cells. , 1988, The Journal of biological chemistry.

[36]  B. Aggarwal,et al.  Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Coleman,et al.  Selective changes in microsomal enzymes of triacylglycerol phosphatidylcholine, and phosphatidylethanolamine biosynthesis during differentiation of 3T3-L1 preadipocytes. , 1978, The Journal of biological chemistry.

[38]  J. Gallin,et al.  Serum lipids in infection. , 1969, The New England journal of medicine.

[39]  G. Hatch,et al.  Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart. , 2005, The Biochemical journal.

[40]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. , 2005, Nature medicine.

[41]  S. Kwak,et al.  NF-kappaB is involved in the TNF-alpha induced inhibition of the differentiation of 3T3-L1 cells by reducing PPARgamma expression. , 2003, Experimental & molecular medicine.

[42]  Kunihiro Matsumoto,et al.  Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. , 2003, Nature cell biology.

[43]  N. Hacohen,et al.  Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. , 2002, Diabetes.

[44]  A. Bowcock,et al.  AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34 , 2002, Nature Genetics.

[45]  R. Surwit,et al.  The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. , 2001, Recent progress in hormone research.

[46]  T. Willson,et al.  Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. , 2001, Endocrinology.

[47]  S. Akira,et al.  Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. , 1997, The EMBO journal.

[48]  J. Gimble,et al.  Decreased expression of murine PPARgamma in adipose tissue during endotoxemia. , 1997, Endocrinology.

[49]  W. Fiers,et al.  Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis. , 1992, Endocrinology.

[50]  G. Bell,et al.  Mammalian facilitative glucose transporter family: structure and molecular regulation. , 1992, Annual review of physiology.

[51]  D. Vance,et al.  Adipose tissue and lipid metabolism , 2022 .