Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor α, and the coactivator peroxisome proliferator-activated receptor γ coactivator-1α
Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor α, and the coactivator peroxisome proliferator-activated receptor γ coactivator-1α
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DOI：
10.1074/jbc.m600931200
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发表时间：
2006-09-08
影响因子：
4.8
通讯作者：
Staudinger, Jeff L.
中科院分区：
文献类型：
--
作者：
Ding, Xunshan;Lichti, Kristin;Staudinger, Jeff L.
动物研究表明，禁食和热量限制会增加特定代谢途径的活性，这些代谢途径与肝脏中的体重减轻有关。有证据表明，这种现象可能部分是通过构成雄烷受体(CAR，NR1I3)的作用发生的。目前，禁食过程中激活CAR的确切分子机制尚不清楚。我们发现，禁食协同诱导了小鼠肝脏中编码过氧化物酶体增殖物激活受体-1α(PGC-1α)、CAR、细胞色素P-450 2b10(Cyp2b10)、UDP-葡萄糖醛酸基转移酶1a1(UGT1a1)、磺基转移酶2a1(Sult2a1)和有机阴离子转运多肽2(Oatp2)的基因的表达。提高细胞内cAMP水平的治疗也会增加培养的肝细胞中这些基因的表达。我们的数据表明，PGC-1α与肝细胞核因子4α(HNF4α，NR2A1)的相互作用是通过位于其近端启动子的一个新的进化保守的HNF4反应元件(HNF4RE)来直接调节CAR基因的表达。PGC-1α在细胞中的表达增加了CAR的表达和非配体依赖的CAR活性。遗传学研究表明，肝脏表达HNF4α是产生禁食诱导的CAR表达和活性所必需的。综上所述，我们的数据表明，禁食通过涉及肝脏中cAMP、PGC-1α、HNF4α、CAR和CAR靶基因的相互作用网络，增加编码关键代谢酶和摄取转运蛋白的基因的表达。鉴于最近的发现，缺乏CAR的小鼠在长时间的热量限制期间对体重减轻的抵抗力显著降低，我们的发现对开发治疗肥胖症和相关疾病的药物具有重要意义。
Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor ( CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1 alpha interaction with hepatocyte nuclear factor 4 alpha(HNF4 alpha, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4RE) located in its proximal promoter. Expression of PGC-1 alpha in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4 alpha is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1 alpha, HNF4 alpha, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.