Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase–Mediated Gluconeogenesis
Tóm tắt
OBJECTIVE—Regulation of phosphoenolpyruvate carboxykinase (PEPCK), the key gene in gluconeogenesis, is critical for glucose homeostasis in response to quick nutritional depletion and/or hormonal alteration.
RESEARCH DESIGN/METHODS AND RESULTS— Here, we identified the testicular orphan nuclear receptor 4 (TR4) as a key PEPCK regulator modulating PEPCK gene via a transcriptional mechanism. TR4 transactivates the 490-bp PEPCK promoter-containing luciferase reporter gene activity by direct binding to the TR4 responsive element (TR4RE) located at −451 to −439 in the promoter region. Binding to TR4RE was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Eliminating TR4 via knockout and RNA interference (RNAi) in hepatocytes significantly reduced the PEPCK gene expression and glucose production in response to glucose depletion. In contrast, ectopic expression of TR4 increased PEPCK gene expression and hepatic glucose production in human and mouse hepatoma cells. Mice lacking TR4 also display reduction of PEPCK expression with impaired gluconeogenesis.
CONCLUSIONS—Together, both in vitro and in vivo data demonstrate the identification of a new pathway, TR4 → PEPCK → gluconeogenesis → blood glucose, which may allow us to modulate metabolic programs via the control of a new key player, TR4, a member of the nuclear receptor superfamily.
Từ khóa
Tài liệu tham khảo
Hanson RW, Reshef L: Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu Rev Biochem 66:581–611,1997
She P, Shiota M, Shelton KD, Chalkley R, Postic C, Magnuson MA: Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Mol Cell Biol 20:6508–6517,2000
Olswang Y, Cohen H, Papo O, Cassuto H, Croniger CM, Hakimi P, Tilghman SM, Hanson RW, Reshef L: A mutation in the peroxisome proliferator-activated receptor gamma-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Proc Natl Acad Sci U S A 99:625–630,2002
Roesler WJ, Vandenbark GR, Hanson RW: Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene. J Biol Chem 264:9657–9664,1989
Giralt M, Park EA, Gurney AL, Liu JS, Hakimi P, Hanson RW: Identification of a thyroid hormone response element in the phosphoenolpyruvate carboxykinase (GTP) gene: evidence for synergistic interaction between thyroid hormone and cAMP cis-regulatory elements. J Biol Chem 266:21991–21996,1991
Imai E, Stromstedt PE, Quinn PG, Carlstedt-Duke J, Gustafsson JA, Granner DK: Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 10:4712–4719,1990
O’Brien RM, Lucas PC, Forest CD, Magnuson MA, Granner DK: Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. Science 249:533–537,1990
Tontonoz P, Hu E, Devine J, Beale EG, Spiegelman BM: PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 15:351–357,1995
Rudic RD, McNamara P, Reilly D, Grosser T, Curtis AM, Price TS, Panda S, Hogenesch JB, FitzGerald GA: Bioinformatic analysis of circadian gene oscillation in mouse aorta. Circulation 112:2716–2724,2005
Mohnike K, Aynsley-Green A: [Hypoglycemia in childhood]. Kinderarztl Prax 61:316–322,1993
Reul BA, Becker DJ, Ongemba LN, Bailey CJ, Henquin JC, Brichard SM: Improvement of glucose homeostasis and hepatic insulin resistance in ob/ob mice given oral molybdate. J Endocrinol 155:55–64,1997
Valera A, Pujol A, Pelegrin M, Bosch F: Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 91:9151–9154,1994
Gomez-Valades AG, Vidal-Alabro A, Molas M, Boada J, Bermudez J, Bartrons R, Perales JC: Overcoming diabetes-induced hyperglycemia through inhibition of hepatic phosphoenolpyruvate carboxykinase (GTP) with RNAi. Mol Ther 13:401–410,2006
Chang C, Da Silva SL, Ideta R, Lee Y, Yeh S, Burbach JP: Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Proc Natl Acad Sci U S A 91:6040–6044,1994
Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM: TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol 8:1667–1680,1994
Lee HJ, Lee YF, Chang C: TR4 orphan receptor represses the human steroid 21-hydroxylase gene expression through the monomeric AGGTCA motif. Biochem Biophys Res Commun 285:1361–1368,2001
Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P: Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci U S A 100:5419–5424,2003
Collins LL, Lee YF, Heinlein CA, Liu NC, Chen YT, Shyr CR, Meshul CK, Uno H, Platt KA, Chang C: Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc Natl Acad Sci U S A 101:15058–15063,2004
Mu X, Lee YF, Liu NC, Chen YT, Kim E, Shyr CR, Chang C: Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis. Mol Cell Biol 24:5887–5899,2004
Chen YT, Collins LL, Uno H, Chang C: Deficits in motor coordination with aberrant cerebellar development in mice lacking testicular orphan nuclear receptor 4. Mol Cell Biol 25:2722–2732,2005
Kim E, Xie S, Yeh SD, Lee YF, Collins LL, Hu YC, Shyr CR, Mu XM, Liu NC, Chen YT, Wang PH, Chang C: Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E/C-I/C-II gene cluster. J Biol Chem 278:46919–46926,2003
Yan ZH, Karam WG, Staudinger JL, Medvedev A, Ghanayem BI, Jetten AM: Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4. J Biol Chem 273:10948–10957,1998
Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ: Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126:789–799,2006
Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM: Nuclear receptor expression links the circadian clock to metabolism. Cell 126:801–810,2006
Wang YJ, Liu HL, Guo HT, Wen HW, Liu J: Primary hepatocyte culture in collagen gel mixture and collagen sandwich. World J Gastroenterol 10:699–702,2004
Lee PD, Giudice LC, Conover CA, Powell DR: Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med 216:319–357,1997
Edwards GE, Jenkins CL, Andrews J: CO(2) assimilation and activities of photosynthetic enzymes in high chlorophyll fluorescence mutants of maize having low levels of ribulose 1,5-bisphosphate carboxylase. Plant Physiol 86:533–539,1988
Bao BY, Yao J, Lee YF: 1Alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 27:1883–1893,2006
Boyd KE, Farnham PJ: Coexamination of site-specific transcription factor binding and promoter activity in living cells. Mol Cell Biol 19:8393–8399,1999
Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M: Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103:843–852,2000
Bennett MK, Osborne TF: Nutrient regulation of gene expression by the sterol regulatory element binding proteins: increased recruitment of gene-specific coregulatory factors and selective hyperacetylation of histone H3 in vivo. Proc Natl Acad Sci U S A 97:6340–6344,2000
Scribner KB, McGrane MM: RNA polymerase II association with the phosphoenolpyruvate carboxykinase (PEPCK) promoter is reduced in vitamin A-deficient mice. J Nutr 133:4112–4117,2003
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408,2001
Harada H, Kuboi Y, Miki R, Honda C, Masushige S, Nakatsuka M, Koga Y, Kato S: Cloning of rabbit TR4 and its bone cell-specific activity to suppress estrogen receptor-mediated transactivation. Endocrinology 139:204–212,1998
Eubank DW, Duplus E, Williams SC, Forest C, Beale EG: Peroxisome proliferator-activated receptor gamma and chicken ovalbumin upstream promoter transcription factor II negatively regulate the phosphoenolpyruvate carboxykinase promoter via a common element. J Biol Chem 276:30561–30569,2001
Roesler WJ, Graham JG, Kolen R, Klemm DJ, McFie PJ: The cAMP response element binding protein synergizes with other transcription factors to mediate cAMP responsiveness. J Biol Chem 270:8225–8232,1995
Waltner-Law M, Duong DT, Daniels MC, Herzog B, Wang XL, Prasad R, Granner DK: Elements of the glucocorticoid and retinoic acid response units are involved in cAMP-mediated expression of the PEPCK gene. J Biol Chem 278:10427–10435,2003
Stafford JM, Waltner-Law M, Granner DK: Role of accessory factors and steroid receptor coactivator 1 in the regulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. J Biol Chem 276:3811–3819,2001
Devine JH, Eubank DW, Clouthier DE, Tontonoz P, Spiegelman BM, Hammer RE, Beale EG: Adipose expression of the phosphoenolpyruvate carboxykinase promoter requires peroxisome proliferator-activated receptor gamma and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo. J Biol Chem 274:13604–13612,1999
Shin DJ, Odom DP, Scribner KB, Ghoshal S, McGrane MM: Retinoid regulation of the phosphoenolpyruvate carboxykinase gene in liver. Mol Cell Endocrinol 195:39–54,2002
She P, Burgess SC, Shiota M, Flakoll P, Donahue EP, Malloy CR, Sherry AD, Magnuson MA: Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation. Diabetes 52:1649–1654,2003