Regulation of triglyceride metabolism by glucocorticoid receptor

Cell & Bioscience

Charles A Harris²  Taiyi Kuo¹  Nora E Gray³  Jen-Chywan Wang¹ 

[1] Graduate Program of Endocrinology, University of California at Berkeley;Department of Medicine, University of California, San Francisco, CA, 94143, USA;Graduate Program of Metabolic Biology, University of California at Berkeley

关键词: Transcription;    Glucocorticoid response Element;    Lipolysis;    Lipogenesis;    Triglyceride;    Glucocorticoid receptor;    Glucocorticoid;   

Others  :  793434
DOI  :  10.1186/2045-3701-2-19

 received in 2012-03-06, accepted in 2012-05-28,  发布年份 2012

【 摘 要 】

Glucocorticoids are steroid hormones that play critical and complex roles in the regulation of triglyceride (TG) homeostasis. Depending on physiological states, glucocorticoids can modulate both TG synthesis and hydrolysis. More intriguingly, glucocorticoids can concurrently affect these two processes in adipocytes. The metabolic effects of glucocorticoids are conferred by intracellular glucocorticoid receptors (GR). GR is a transcription factor that, upon binding to glucocorticoids, regulates the transcriptional rate of specific genes. These GR primary target genes further initiate the physiological and pathological responses of glucocorticoids. In this article, we overview glucocorticoid-regulated genes, especially those potential GR primary target genes, involved in glucocorticoid-regulated TG metabolism. We also discuss transcriptional regulators that could act with GR to participate in these processes. This knowledge is not only important for the fundamental understanding of steroid hormone actions, but also are essential for future therapeutic interventions against metabolic diseases associated with aberrant glucocorticoid signaling, such as insulin resistance, dyslipidemia, central obesity and hepatic steatosis.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Berdanier CD: Role of glucocorticoids in the regulation of lipogenesis. Faseb J 1989, 3:2179-2183.
• [2]Berdanier CD, Wurdeman R, Tobin RB: Further studies on the role of the adrenal hormones in responses of rats to meal-feeding. J Nutr 1976, 106:1791-1800.
• [3]Bouillon DJ, Berdanier CD: Role of glucocorticoid in adaptive hyperlipogenesis in the rat. J Nutr 1980, 110:286-297.
• [4]Wurdeman R, Berdanier CD, Tobin RB: Enzyme overshoot in starved-refed rats: role of the adrenal glucocorticoid. J Nutr 1978, 108:1457-1461.
• [5]Arnaldi G, Scandali VM, Trementino L, Cardinaletti M, Appolloni G, Boscaro M: Pathophysiology of dyslipidemia in Cushing’s syndrome. Neuroendocrinology 2010, 92(Suppl 1):86-90.
• [6]Chanson P, Salenave S: Metabolic syndrome in Cushing’s syndrome. Neuroendocrinology 2010, 92(Suppl 1):96-101.
• [7]Yu CY, Mayba O, Lee JV, Tran J, Harris C, Speed TP, Wang JC: Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLoS One 2010, 5:e15188.
• [8]Macfarlane DP, Forbes S, Walker BR: Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol 2008, 197:189-204.
• [9]Samuel VT, Petersen KF, Shulman GI: Lipid-induced insulin resistance: unravelling the mechanism. Lancet 2010, 375:2267-2277.
• [10]Petersen KF, Shulman GI: Etiology of insulin resistance. Am J Med 2006, 119:S10-S16.
• [11]Taylor AI, Frizzell N, McKillop AM, Flatt PR, Gault VA: Effect of RU486 on hepatic and adipocyte gene expression improves diabetes control in obesity-type 2 diabetes. Horm Metab Res 2009, 41:899-904.
• [12]Morton NM, Holmes MC, Fievet C, Staels B, Tailleux A, Mullins JJ, Seckl JR: Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 2001, 276:41293-41300.
• [13]Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR: Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 2004, 53:931-938.
• [14]Kershaw EE, Morton NM, Dhillon H, Ramage L, Seckl JR, Flier JS: Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity. Diabetes 2005, 54:1023-1031.
• [15]Berthiaume M, Laplante M, Festuccia WT, Cianflone K, Turcotte LP, Joanisse DR, Olivecrona G, Thieringer R, Deshaies Y: 11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues. Am J Physiol Endocrinol Metab 2007, 293:E1045-E1052.
• [16]Li G, Hernandez-Ono A, Crooke RM, Graham MJ, Ginsberg HN: Effects of antisense-mediated inhibition of 11beta-hydroxysteroid dehydrogenase type 1 on hepatic lipid metabolism. J Lipid Res 2011, 52:971-981.
• [17]Nuotio-Antar AM, Hachey DL, Hasty AH: Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice. Am J Physiol Endocrinol Metab 2007, 293:E1517-E1528.
• [18]Newton R, Holden NS: Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol Pharmacol 2007, 72:799-809.
• [19]Glass CK, Saijo K: Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 2010, 10:365-376.
• [20]Steger DJ, Grant GR, Schupp M, Tomaru T, Lefterova MI, Schug J, Manduchi E, Stoeckert CJ, Lazar MA: Propagation of adipogenic signals through an epigenomic transition state. Genes Dev 2010, 24:1035-1044.
• [21]Siersbaek R, Nielsen R, John S, Sung MH, Baek S, Loft A, Hager GL, Mandrup S: Extensive chromatin remodelling and establishment of transcription factor’hotspots’ during early adipogenesis. Embo J 2011, 30:1459-1472.
• [22]Reddy TE, Pauli F, Sprouse RO, Neff NF, Newberry KM, Garabedian MJ, Myers RM: Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res 2009, 19:2163-2171.
• [23]Slavin BG, Ong JM, Kern PA: Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes. J Lipid Res 1994, 35:1535-1541.
• [24]Gathercole LL, Morgan SA, Bujalska IJ, Hauton D, Stewart PM, Tomlinson JW: Regulation of lipogenesis by glucocorticoids and insulin in human adipose tissue. PLoS One 2011, 6:e26223.
• [25]Xu C, He J, Jiang H, Zu L, Zhai W, Pu S, Xu G: Direct effect of glucocorticoids on lipolysis in adipocytes. Mol Endocrinol 2009, 23:1161-1170.
• [26]Zhao LF, Iwasaki Y, Zhe W, Nishiyama M, Taguchi T, Tsugita M, Kambayashi M, Hashimoto K, Terada Y: Hormonal regulation of acetyl-CoA carboxylase isoenzyme gene transcription. Endocr J 2010, 57:317-324.
• [27]Sul HS, Wang D: Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu Rev Nutr 1998, 18:331-351.
• [28]Lu Z, Gu Y, Rooney SA: Transcriptional regulation of the lung fatty acid synthase gene by glucocorticoid, thyroid hormone and transforming growth factor-beta 1. Biochim Biophys Acta 2001, 1532:213-222.
• [29]Soncini M, Yet SF, Moon Y, Chun JY, Sul HS: Hormonal and nutritional control of the fatty acid synthase promoter in transgenic mice. J Biol Chem 1995, 270:30339-30343.
• [30]Kirk CJ, Verrinder TR, Hems DA: Fatty acid synthesis in the perfused liver of adrenalectomized rats. Biochem J 1976, 156:593-602.
• [31]Amatruda JM, Danahy SA, Chang CL: The effects of glucocorticoids on insulin-stimulated lipogenesis in primary cultures of rat hepatocytes. Biochem J 1983, 212:135-141.
• [32]Wang Y, Jones Voy B, Urs S, Kim S, Soltani-Bejnood M, Quigley N, Heo YR, Standridge M, Andersen B, Dhar M, et al.: The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr 2004, 134:1032-1038.
• [33]Travers MT, Barber MC: Insulin-glucocorticoid interactions in the regulation of acetyl-CoA carboxylase-alpha transcript diversity in ovine adipose tissue. J Mol Endocrinol 1999, 22:71-79.
• [34]Dolinsky VW, Douglas DN, Lehner R, Vance DE: Regulation of the enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid dexamethasone. Biochem J 2004, 378:967-974.
• [35]Zhang P, O’Loughlin L, Brindley DN, Reue K: Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis. J Lipid Res 2008, 49:1519-1528.
• [36]Jennings RJ, Lawson N, Fears R, Brindley DN: Stimulation of the activities of phosphatidate phosphohydrolase and tyrosine aminotransferase in rat hepatocytes by glucocorticoids. FEBS Lett 1981, 133:119-122.
• [37]Pittner RA, Fears R, Brindley DN: Interactions of insulin, glucagon and dexamethasone in controlling the activity of glycerol phosphate acyltransferase and the activity and subcellular distribution of phosphatidate phosphohydrolase in cultured rat hepatocytes. Biochem J 1985, 230:525-534.
• [38]Legrand P, Catheline D, Hannetel JM, Lemarchal P: Stearoyl-CoA desaturase activity in primary culture of chicken hepatocytes. Influence of insulin, glucocorticoid, fatty acids and cordycepin. Int J Biochem 1994, 26:777-785.
• [39]Dich J, Bro B, Grunnet N, Jensen F, Kondrup J: Accumulation of triacylglycerol in cultured rat hepatocytes is increased by ethanol and by insulin and dexamethasone. Biochem J 1983, 212:617-623.
• [40]Mangiapane EH, Brindley DN: Effects of dexamethasone and insulin on the synthesis of triacylglycerols and phosphatidylcholine and the secretion of very-low-density lipoproteins and lysophosphatidylcholine by monolayer cultures of rat hepatocytes. Biochem J 1986, 233:151-160.
• [41]Kansara MS, Mehra AK, Von Hagen J, Kabotyansky E, Smith PJ: Physiological concentrations of insulin and T3 stimulate 3 T3-L1 adipocyte acyl-CoA synthetase gene transcription. Am J Physiol 1996, 270:E873-E881.
• [42]Shan D, Li JL, Wu L, Li D, Hurov J, Tobin JF, Gimeno RE, Cao J: GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis. J Lipid Res 2010, 51:1971-1981.
• [43]Fried SK, Russell CD, Grauso NL, Brolin RE: Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest 1993, 92:2191-2198.
• [44]Appel B, Fried SK: Effects of insulin and dexamethasone on lipoprotein lipase in human adipose tissue. Am J Physiol 1992, 262:E695-E699.
• [45]Mead JR, Ramji DP: The pivotal role of lipoprotein lipase in atherosclerosis. Cardiovasc Res 2002, 55:261-269.
• [46]Manmontri B, Sariahmetoglu M, Donkor J, Bou Khalil M, Sundaram M, Yao Z, Reue K, Lehner R, Brindley DN: Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically. J Lipid Res 2008, 49:1056-1067.
• [47]Takeuchi K, Reue K: Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol Endocrinol Metab 2009, 296:E1195-E1209.
• [48]Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC, Kelly DP: Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 2006, 4:199-210.
• [49]Campbell JE, Peckett AJ, D’Souza AM, Hawke TJ, Riddell MC: Adipogenic and lipolytic effects of chronic glucocorticoid exposure. Am J Physiol Cell Physiol 2011, 300:C198-C209.
• [50]Chakrabarti P, Kandror KV: FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes. J Biol Chem 2009, 284:13296-13300.
• [51]Lee MJ, Gong DW, Burkey BF, Fried SK: Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study. Am J Physiol Endocrinol Metab 2011, 300:E571-E580.
• [52]Waddell DS, Baehr LM, van den Brandt J, Johnsen SA, Reichardt HM, Furlow JD, Bodine SC: The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am J Physiol Endocrinol Metab 2008, 295:E785-E797.
• [53]Nishimura M, Mikura M, Hirasaka K, Okumura Y, Nikawa T, Kawano Y, Nakayama M, Ikeda M: Effects of dimethyl sulphoxide and dexamethasone on mRNA expression of myogenesis- and muscle proteolytic system-related genes in mouse myoblastic C2C12 cells. J Biochem 2008, 144:717-724.
• [54]Kershaw EE, Hamm JK, Verhagen LA, Peroni O, Katic M, Flier JS: Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes 2006, 55:148-157.
• [55]Kralisch S, Klein J, Lossner U, Bluher M, Paschke R, Stumvoll M, Fasshauer M: Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3 T3-L1 adipocytes. Mol Cell Endocrinol 2005, 240:43-49.
• [56]Lampidonis AD, Rogdakis E, Voutsinas GE, Stravopodis DJ: The resurgence of Hormone-Sensitive Lipase (HSL) in mammalian lipolysis. Gene 2011, 477:1-11.
• [57]Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS: Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol 2007, 293:G1-G4.
• [58]Kraemer FB, Shen WJ: Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res 2002, 43:1585-1594.
• [59]Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS: Regulation of lipolysis in adipocytes. Annu Rev Nutr 2007, 27:79-101.
• [60]Brasaemle DL, Subramanian V, Garcia A, Marcinkiewicz A, Rothenberg A: Perilipin A and the control of triacylglycerol metabolism. Mol Cell Biochem 2009, 326:15-21.
• [61]Di S, Maxson MM, Franco A, Tasker JG: Glucocorticoids regulate glutamate and GABA synapse-specific retrograde transmission via divergent nongenomic signaling pathways. J Neurosci 2009, 29:393-401.
• [62]Gray NE, Lam LN, Yang K, Zhou AY, Koliwad S, Wang JC: Angiopoietin-like 4 (Angptl4) is a physiological mediator of intracellular lipolysis in murine Adipocytes. J Biol Chem 2012, 287:8444-8456.
• [63]Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M: Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol Cell Biol 1999, 19:6286-6296.
• [64]Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, Monks BR, Birnbaum MJ: Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol 2010, 30:5009-5020.
• [65]Koliwad SK, Kuo T, Shipp LE, Gray NE, Backhed F, So AY, Farese RV, Wang JC: Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism. J Biol Chem 2009, 284:25593-25601.
• [66]Mattijssen F, Kersten S: Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta 2012, 1821:782-789.
• [67]Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML, Liu Q: The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. J Biol Chem 2009, 284:1419-1424.
• [68]Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, Tan CK, Huang RL, Sze SK, Tang MB, et al.: Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing. J Biol Chem 2010, 285:32999-33009.
• [69]Goh YY, Pal M, Chong HC, Zhu P, Tan MJ, Punugu L, Lam CR, Yau YH, Tan CK, Huang RL, et al.: Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration. Am J Pathol 2010, 177:2791-2803.
• [70]Yang YH, Wang Y, Lam KS, Yau MH, Cheng KK, Zhang J, Zhu W, Wu D, Xu A: Suppression of the Raf/MEK/ERK signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4. Arterioscler Thromb Vasc Biol 2008, 28:835-840.
• [71]Kim HK, Youn BS, Shin MS, Namkoong C, Park KH, Baik JH, Kim JB, Park JY, Lee KU, Kim YB, Kim MS: Hypothalamic angptl4/fiaf is a novel regulator of food intake and body weight. Diabetes 2010, 59:2772-2780.
• [72]So AY, Chaivorapol C, Bolton EC, Li H, Yamamoto KR: Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS Genet 2007, 3:e94.
• [73]Yamada T, Ozaki N, Kato Y, Miura Y, Oiso Y: Insulin downregulates angiopoietin-like protein 4 mRNA in 3 T3-L1 adipocytes. Biochem Biophys Res Commun 2006, 347:1138-1144.
• [74]Savage DB, Semple RK: Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance. Curr Opin Lipidol 2010, 21:329-336.
• [75]Jornayvaz FR, Samuel VT, Shulman GI: The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu Rev Nutr 2010, 30:273-290.
• [76]Lemke U, Krones-Herzig A, Berriel Diaz M, Narvekar P, Ziegler A, Vegiopoulos A, Cato AC, Bohl S, Klingmuller U, Screaton RA, et al.: The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell Metab 2008, 8:212-223.
• [77]Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, et al.: Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007, 5:415-425.
• [78]Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B: Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009, 89:147-191.
• [79]Rose AJ, Diaz MB, Reimann A, Klement J, Walcher T, Krones-Herzig A, Strobel O, Werner J, Peters A, Kleyman A, et al.: Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor. Cell Metab 2011, 14:123-130.
• [80]Chen W, Roeder RG: The Mediator subunit MED1/TRAP220 is required for optimal glucocorticoid receptor-mediated transcription activation. Nucleic Acids Res 2007, 35:6161-6169.
• [81]Chen W, Roeder RG: Mediator-dependent nuclear receptor function. Semin Cell Dev Biol 2010, 22:749-758.
• [82]Chen W, Rogatsky I, Garabedian MJ: MED14 and MED1 differentially regulate target-specific gene activation by the glucocorticoid receptor. Mol Endocrinol 2006, 20:560-572.
• [83]Kim JH, Yang CK, Heo K, Roeder RG, An W, Stallcup MR: CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes. Mol Cell 2008, 31:510-519.
• [84]Jia Y, Viswakarma N, Fu T, Yu S, Rao MS, Borensztajn J, Reddy JK: Conditional ablation of mediator subunit MED1 (MED1/PPARBP) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone-induced hepatic steatosis. Gene Expr 2009, 14:291-306.
• [85]Rogatsky I, Zarember KA, Yamamoto KR: Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. Embo J 2001, 20:6071-6083.
• [86]Patel R, Patel M, Tsai R, Lin V, Bookout AL, Zhang Y, Magomedova L, Li T, Chan JF, Budd C, et al.: LXRbeta is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J Clin Invest 2010, 121:431-441.
• [87]Nader N, Ng SS, Wang Y, Abel BS, Chrousos GP, Kino T: Liver X Receptors Regulate the Transcriptional Activity of the Glucocorticoid Receptor: Implications for the Carbohydrate Metabolism. PLoS One 2012, 7:e26751.
• [88]Lucas PC, Granner DK: Hormone response domains in gene transcription. Annu Rev Biochem 1992, 61:1131-1173.
• [89]Miner JN, Yamamoto KR: Regulatory crosstalk at composite response elements. Trends Biochem Sci 1991, 16:423-426.
• [90]Nakae J, Kitamura T, Silver DL, Accili D: The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 2001, 108:1359-1367.
• [91]Nakae J, Oki M, Cao Y: The FoxO transcription factors and metabolic regulation. FEBS Lett 2008, 582:54-67.