PGC-1α调节黄体生成素和醛固酮合成以及葡萄糖激酶表达的分子机制研究
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摘要
第一部分PGC-1α协同SF-1调节黄体生成素和醛固酮合成的研究
过氧化物酶体增殖激活受体γ共激活因子1α(PGC-1α)能共刺激多种转录因子从而调节能量代谢进程。核受体类固醇激素生成因子(SF-1)在垂体、性腺、肾上腺等内分泌组织中高表达,转录调控多种关键基因,同时调节下丘脑-垂体-性腺轴多水平的激素合成。为探索PGC-1α在类固醇激素合成及垂体激素分泌中的作用,本课题以小鼠垂体促性腺αT3-1细胞为研究模型,过表达PGC-1α后,通过real-time PCR实验检测到LHβ和αGSU在水mRNA平的表达量升高,又进一步通过酶联免疫吸附试验(ELISA)证明,PGC-1α刺激αT3-1细胞分泌的黄体生成素增加。分析LHp启动子序列,发现-127 bp～-119 bp位点存在一个SF-1结合元件突变该元件后,双荧光报告实验证明SF-1和PGC-1α对LHβ启动子的刺激作GSE (gonadotrope-specific element),用全部消失。染色质免疫沉淀实验证明PGC-1α与SF-1共定位在LHβ启动子区含GSE元件的区域,并促进LHβ转录。为进一步证明PGC-1α对SF-1的共刺激作用,分析了二者相互作用的分
子机制。哺乳动物双杂交实验和免疫共沉淀实验证明PGC-1α与SF-1能在体内形成复合物,进一步实验证明二者能直接相互作用。该作用GST pull-down发生在PGC-1α的N端1～180氨基酸区域(含LXXLL模体,142～146氨基酸)与SF-1 C端187～462氨基酸区之间。构建不同长度的SF-1基因表达片段发现,只有当SF-1的最适激活结构域和AF-2结(proximal activation domain)构域同时存在时,PGC-1α和SF-1才能直接结合。肾上腺皮质是最主要的类固醇激素合成部位,细胞色素P450家族成员在
此参与胆固醇代谢、类固醇激素合成的多个催化反应。Cyp11b2基因编码的蛋白质产物负责催化醛固酮合成的最后三步反应,是醛固酮合成的限速酶。在小鼠肾上腺皮质Y-1细胞中,real-time PCR实验证明,PGC-1α能促使Cyp11b2,Cyp11b1和P450scc基因在mRNA水平表达上调,ELISA实验进一步检测到PGC-1α协同SF-1促进细胞醛固酮的分泌。
另一方面,通过双荧光报告实验检测到PGC-1α与雌激素受体相关受体家族成员ERRα和ERRγ共同促进SF-1转录,在过表达PGC-1α的αT3-1细胞和Y-1细胞中,SF-1在mRNA水平和蛋白质水平的表达量均显著提高。综上所述,本课题揭示了PGC-1α在类固醇激素和促性腺激素合成中具有重要的调节作用,分析了其刺激激素合成的分子机制,提示PGC-1α可能通过SF-1调节性腺和肾上腺的发育以及性别分化。
第二部分PGC-1α协同ERRα调节葡萄糖激酶表达的研究
过氧化物酶体增殖激活受体γ共激活因子1α(PGC-1α)是细胞能量代谢的关键调节子。它通过共激活多种核受体和转录因子,调节适应性产热、肝糖异生、脂肪酸氧化及线粒体生物合成等生理进程。葡萄糖激酶是一种存在于哺乳动物肝脏和胰腺中分子量为50 KDa的蛋白质,也被称为Ⅳ型己糖激酶,是糖酵解过程中第一个限速酶。它在调节肝脏葡萄糖利用中发挥重要的作用,并接受胰岛素信号刺激。
本课题研究发现,大鼠葡萄糖激酶(glucokinase,Gck)启动子区存在一个保守的雌激素受体相关受体的结合元件ERRE(-52 bp～-39 bp),双荧光报告实验分析了截短和位点突变的Gck启动子,证明PGC-1α和ERRα能利用该元件刺激Gck启动子的活性。EMSA实验进一步证明ERRα能在体外结合ERRE元件,ChIP实验则证实PGC-1α和ERRα共同定位在大鼠肝细胞Gck启动子含该元件的区域,表明PGC-1α和ERRα通过ERRE元件促进大鼠肝脏Gck基因转录。大鼠肝原代细胞感染PGC-1α和ERRα腺病毒后,Gck基因在mRNA和蛋白质水平表达量均明显上调。同时,Gck的催化活性大大增加,这表明PGC-1α和ERRα在调节葡萄糖代谢方面发挥着重要的作用。PGC-1α和ERRα对Gck的促进作用还可以增强胰岛素刺激的效应。最后,引入ERRα特异的siRNA (siERRα)和拮抗剂XCT790抑制ERRα表达后,胰岛素诱导的Gck表达受到影响,充分证明了ERRα介导了胰岛素诱导的Gck表达。综上所述,本研究发现了PGC-1α和ERRα对Gck的促进作用及对肝脏葡萄糖代谢的影响,证明ERRα在胰岛素刺激葡萄糖激酶通路中的作用,并可以促进Ⅱ型糖尿病葡萄糖稳态的形成。
Peroxisome proliferators-activated receptor y coactivator-la (PGC-la) is capable of coactivating a number of nuclear receptors and other transcription factors involved in the regulation of multiple metabolic processes. The orphan nuclear receptor steroidogenic factor 1 (SF-1) is highly expressed in the pituitary, gonad and adrenal gland. To date, it is the only transcription factor demonstrated to play the key roles at all levels of the hypothalamic-pituitary-steroidogenic tissue axis.
In the present study, we demonstrated that PGC-la interacts with and coactivates SF-1 to induce LHβand aGSU gene expression, subsequently leading to the increased secrection of LH in pituitary gonadotrope-derivedαT3-1 cells. PGC-la-induced activation of LHβexpression occurs at its transcription level that is mediated by an SF-1 binding element (GSE) mapped in the promoter region of LHβgene. Our ChIP assays confirm the binding of SF-1 to PGC-la-responsive element and that PGC-la is presumably recruited to LHβpromoter region through interaction with SF-1. Mammalian two-hybrid and coimmunoprecipitation (CoIP) assays demonstrated PGC-la interaction with SF-1 in vivo. Furthermore, GST pull-down experiments indicated PGC-la interacts with SF-1 through its N-terminal fragment (1-180 amino acid) containing containing LXXLL domain and that SF-1 interacts with PGC-1αthrough its C-terminal fragment (187-462 amino acid) containing proximal activation domain and AF-2 domain. Additionally, PGC-1αalso stimulates the expression of Cyp11b2, Cyp11b1 and P450scc, as well as synthesis of aldosterone in adrenal cortex-derived Y-1 cells. In addition to coactivation of SF-1, PGC-1αwas demonstrated to induce SF-1 gene expression in αT3-1 and Y-1 cells.
Based on these data, we proposed a model of mechanism of PGC-1αaction on LH synthesis and steroidogenesis in cells. PGC-la coactivates ERRs or other factors to induce SF-1 gene expression, meanwhile, it interacts directly with and coactivates SF-1 to stimulate its target genes. Given that SF-1 is a key regulator of endocrine function within hypothalamic-pituitary-gonadal reproductive axis and adrenal cortex, it is reasonable to propose that PGC-la may play important roles in steroidogenesis, gonad development and sex differentiation in these tissues through SF-1. Our studies revealed the potential role of PGC-1αand suggested PGC-1αhas much broader effects in endocrine system, more than energy metabolism, glucose and fatty acid metabolism.
Peroxisome proliferator-activated receptor coactivator-1α(PGC-1α) is a key regulator of cellular energy metabolism, and regulates processes such as adaptive thermogenesis, hepatic gluconeogenesis, fatty acid oxidation and mitochondrial biogenesis by coactivating numerous nuclear receptors and transcription factors. Here, we demonstrate the presence of ERRa binding site in the regulatory sequence of the glucokinase gene and that PGC-1αcoactivates ERRαto stimulate the transcription of glucokinase. Simultaneous over-expression of PGC-1αand ERRa potently induced the glucokinase gene expression and its enzymatic activity in primary hepatocytes; however, expression of either PGC-1αor ERRαalone had no significant effect. Electrophoretic mobility shift and chromatin immuno-precipitation assays revealed the interaction of ERRαwith the glucokinase promoter. Finally, the knockdown of endogenous ERRαwith specific siRNA (siERRα) or pharmacological inhibition of ERRαwith XCT790 attenuated insulin-induced glucokinase expression. Taken together, this research identifies glucokinase as a novel target of PGC-1α/ERRα, and underscores the regulatory function of ERRαin insulin-dependent enzyme regulation.
过氧化物酶体增殖激活受体γ共激活因子1α(PGC-1α)能共刺激多种转录因子从而调节能量代谢进程。核受体类固醇激素生成因子(SF-1)在垂体、性腺、肾上腺等内分泌组织中高表达,转录调控多种关键基因,同时调节下丘脑-垂体-性腺轴多水平的激素合成。为探索PGC-1α在类固醇激素合成及垂体激素分泌中的作用,本课题以小鼠垂体促性腺αT3-1细胞为研究模型,过表达PGC-1α后,通过real-time PCR实验检测到LHβ和αGSU在水mRNA平的表达量升高,又进一步通过酶联免疫吸附试验(ELISA)证明,PGC-1α刺激αT3-1细胞分泌的黄体生成素增加。分析LHp启动子序列,发现-127 bp～-119 bp位点存在一个SF-1结合元件突变该元件后,双荧光报告实验证明SF-1和PGC-1α对LHβ启动子的刺激作GSE (gonadotrope-specific element),用全部消失。染色质免疫沉淀实验证明PGC-1α与SF-1共定位在LHβ启动子区含GSE元件的区域,并促进LHβ转录。为进一步证明PGC-1α对SF-1的共刺激作用,分析了二者相互作用的分
子机制。哺乳动物双杂交实验和免疫共沉淀实验证明PGC-1α与SF-1能在体内形成复合物,进一步实验证明二者能直接相互作用。该作用GST pull-down发生在PGC-1α的N端1～180氨基酸区域(含LXXLL模体,142～146氨基酸)与SF-1 C端187～462氨基酸区之间。构建不同长度的SF-1基因表达片段发现,只有当SF-1的最适激活结构域和AF-2结(proximal activation domain)构域同时存在时,PGC-1α和SF-1才能直接结合。肾上腺皮质是最主要的类固醇激素合成部位,细胞色素P450家族成员在
此参与胆固醇代谢、类固醇激素合成的多个催化反应。Cyp11b2基因编码的蛋白质产物负责催化醛固酮合成的最后三步反应,是醛固酮合成的限速酶。在小鼠肾上腺皮质Y-1细胞中,real-time PCR实验证明,PGC-1α能促使Cyp11b2,Cyp11b1和P450scc基因在mRNA水平表达上调,ELISA实验进一步检测到PGC-1α协同SF-1促进细胞醛固酮的分泌。
另一方面,通过双荧光报告实验检测到PGC-1α与雌激素受体相关受体家族成员ERRα和ERRγ共同促进SF-1转录,在过表达PGC-1α的αT3-1细胞和Y-1细胞中,SF-1在mRNA水平和蛋白质水平的表达量均显著提高。综上所述,本课题揭示了PGC-1α在类固醇激素和促性腺激素合成中具有重要的调节作用,分析了其刺激激素合成的分子机制,提示PGC-1α可能通过SF-1调节性腺和肾上腺的发育以及性别分化。
第二部分PGC-1α协同ERRα调节葡萄糖激酶表达的研究
过氧化物酶体增殖激活受体γ共激活因子1α(PGC-1α)是细胞能量代谢的关键调节子。它通过共激活多种核受体和转录因子,调节适应性产热、肝糖异生、脂肪酸氧化及线粒体生物合成等生理进程。葡萄糖激酶是一种存在于哺乳动物肝脏和胰腺中分子量为50 KDa的蛋白质,也被称为Ⅳ型己糖激酶,是糖酵解过程中第一个限速酶。它在调节肝脏葡萄糖利用中发挥重要的作用,并接受胰岛素信号刺激。
本课题研究发现,大鼠葡萄糖激酶(glucokinase,Gck)启动子区存在一个保守的雌激素受体相关受体的结合元件ERRE(-52 bp～-39 bp),双荧光报告实验分析了截短和位点突变的Gck启动子,证明PGC-1α和ERRα能利用该元件刺激Gck启动子的活性。EMSA实验进一步证明ERRα能在体外结合ERRE元件,ChIP实验则证实PGC-1α和ERRα共同定位在大鼠肝细胞Gck启动子含该元件的区域,表明PGC-1α和ERRα通过ERRE元件促进大鼠肝脏Gck基因转录。大鼠肝原代细胞感染PGC-1α和ERRα腺病毒后,Gck基因在mRNA和蛋白质水平表达量均明显上调。同时,Gck的催化活性大大增加,这表明PGC-1α和ERRα在调节葡萄糖代谢方面发挥着重要的作用。PGC-1α和ERRα对Gck的促进作用还可以增强胰岛素刺激的效应。最后,引入ERRα特异的siRNA (siERRα)和拮抗剂XCT790抑制ERRα表达后,胰岛素诱导的Gck表达受到影响,充分证明了ERRα介导了胰岛素诱导的Gck表达。综上所述,本研究发现了PGC-1α和ERRα对Gck的促进作用及对肝脏葡萄糖代谢的影响,证明ERRα在胰岛素刺激葡萄糖激酶通路中的作用,并可以促进Ⅱ型糖尿病葡萄糖稳态的形成。
Peroxisome proliferators-activated receptor y coactivator-la (PGC-la) is capable of coactivating a number of nuclear receptors and other transcription factors involved in the regulation of multiple metabolic processes. The orphan nuclear receptor steroidogenic factor 1 (SF-1) is highly expressed in the pituitary, gonad and adrenal gland. To date, it is the only transcription factor demonstrated to play the key roles at all levels of the hypothalamic-pituitary-steroidogenic tissue axis.
In the present study, we demonstrated that PGC-la interacts with and coactivates SF-1 to induce LHβand aGSU gene expression, subsequently leading to the increased secrection of LH in pituitary gonadotrope-derivedαT3-1 cells. PGC-la-induced activation of LHβexpression occurs at its transcription level that is mediated by an SF-1 binding element (GSE) mapped in the promoter region of LHβgene. Our ChIP assays confirm the binding of SF-1 to PGC-la-responsive element and that PGC-la is presumably recruited to LHβpromoter region through interaction with SF-1. Mammalian two-hybrid and coimmunoprecipitation (CoIP) assays demonstrated PGC-la interaction with SF-1 in vivo. Furthermore, GST pull-down experiments indicated PGC-la interacts with SF-1 through its N-terminal fragment (1-180 amino acid) containing containing LXXLL domain and that SF-1 interacts with PGC-1αthrough its C-terminal fragment (187-462 amino acid) containing proximal activation domain and AF-2 domain. Additionally, PGC-1αalso stimulates the expression of Cyp11b2, Cyp11b1 and P450scc, as well as synthesis of aldosterone in adrenal cortex-derived Y-1 cells. In addition to coactivation of SF-1, PGC-1αwas demonstrated to induce SF-1 gene expression in αT3-1 and Y-1 cells.
Based on these data, we proposed a model of mechanism of PGC-1αaction on LH synthesis and steroidogenesis in cells. PGC-la coactivates ERRs or other factors to induce SF-1 gene expression, meanwhile, it interacts directly with and coactivates SF-1 to stimulate its target genes. Given that SF-1 is a key regulator of endocrine function within hypothalamic-pituitary-gonadal reproductive axis and adrenal cortex, it is reasonable to propose that PGC-la may play important roles in steroidogenesis, gonad development and sex differentiation in these tissues through SF-1. Our studies revealed the potential role of PGC-1αand suggested PGC-1αhas much broader effects in endocrine system, more than energy metabolism, glucose and fatty acid metabolism.
Peroxisome proliferator-activated receptor coactivator-1α(PGC-1α) is a key regulator of cellular energy metabolism, and regulates processes such as adaptive thermogenesis, hepatic gluconeogenesis, fatty acid oxidation and mitochondrial biogenesis by coactivating numerous nuclear receptors and transcription factors. Here, we demonstrate the presence of ERRa binding site in the regulatory sequence of the glucokinase gene and that PGC-1αcoactivates ERRαto stimulate the transcription of glucokinase. Simultaneous over-expression of PGC-1αand ERRa potently induced the glucokinase gene expression and its enzymatic activity in primary hepatocytes; however, expression of either PGC-1αor ERRαalone had no significant effect. Electrophoretic mobility shift and chromatin immuno-precipitation assays revealed the interaction of ERRαwith the glucokinase promoter. Finally, the knockdown of endogenous ERRαwith specific siRNA (siERRα) or pharmacological inhibition of ERRαwith XCT790 attenuated insulin-induced glucokinase expression. Taken together, this research identifies glucokinase as a novel target of PGC-1α/ERRα, and underscores the regulatory function of ERRαin insulin-dependent enzyme regulation.
引文
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41. Ferre T, Riu E, Bosch F, et al. Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver. Faseb J,1996,10:1213-1218.
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43. Magnuson MA. Glucokinase gene structure. Functional implications of molecular genetic studies. Diabetes,1990,39:523-527.
44. Iynedjian PB. Mammalian glucokinase and its gene. Biochem J,1993,293 (Pt 1):1-13.
45. Printz RL, Magnuson MA, Granner DK. Mammalian glucokinase. Annu Rev Nutr,1993,13:463-496.
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50. Sladek R, Bader JA, Giguere V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol,1997,17:5400-5409.
51. Vega RB, Kelly DP. A role for estrogen-related receptor alpha in the control of mitochondrial fatty acid beta-oxidation during brown adipocyte differentiation. J Biol Chem,1997,272:31693-31699.
52. Kamei Y, Ohizumi H, Fujitani Y, et al. PPARgamma coactivator lbeta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci U S A,2003,100: 12378-12383.
53. Schreiber SN, Emter R, Hock MB, et al. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1 alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci U S A, 2004,101:6472-6477.
54. Wang YJ, Liu HL, Guo HT, et al. Primary hepatocyte culture in collagen gel mixture and collagen sandwich. World J Gastroenterol,2004,10:699-702.
55. Berger K, Lindh R, Wierup N, et al. Phosphodiesterase 3B is localized in caveolae and smooth ER in mouse hepatocytes and is important in the regulation of glucose and lipid metabolism. PLoS One,2009,4:e4671.
56. Trus MD, Zawalich WS, Burch PT, et al. Regulation of glucose metabolism in pancreatic islets. Diabetes,1981,30:911-922.
57. Davidson AL, Arion WJ. Factors underlying significant underestimations of glucokinase activity in crude liver extracts:physiological implications of higher cellular activity. Arch Biochem Biophys,1987,253:156-167.
58. Kim SY, Kim HI, Park SK, et al. Liver glucokinase can be activated by peroxisome proliferator-activated receptor-gamma. Diabetes,2004,53 Suppl 1: S66-70.
59. Roth U, Curth K, Unterman TG, et al. The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem,2004,279:2623-2631.
60. Wende AR, Huss JM, Schaeffer PJ, et al. PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha:a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol,2005,25: 10684-10694.
61. Foretz M, Guichard C, Ferre P, et al. Sterol regulatory element binding protein-lc is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A,1999,96: 12737-12742.
62. Kim SY, Kim HI, Kim TH, et al. SREBP-lc mediates the insulin-dependent hepatic glucokinase expression. J Biol Chem,2004,279:30823-30829.
63. Gregori C, Guillet-Deniau I, Girard J, et al. Insulin regulation of glucokinase gene expression:evidence against a role for sterol regulatory element binding protein 1 in primary hepatocytes. FEBS Lett,2006,580:410-414.
64. Herzog B, Cardenas J, Hall RK, et al. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem,2006,281:99-106.
65. Willy PJ, Murray IR, Qian J, et al. Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. Proc Natl Acad Sci U S A,2004,101:8912-8917.
66. Girard J, Ferre P, Foufelle F. Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Annu Rev Nutr,1997, 17:325-352.
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