Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity.
Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity.
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作者：
Kim E;Liu NC;Yu IC;Lin HY;Lee YF;Sparks JD;Chen LM;Chang C
TR4是一种核受体，没有明确的病理生理作用。我们在体内和体外研究了肝脏TR4在脂肪生成和胰岛素敏感性调节中的作用。用肝细胞和不同的TR4野生型和突变型构建物进行TR4活性和磷酸化分析。对TR4基因敲除小鼠、C57BL/6小鼠和db/db小鼠的肝组织进行了研究，以研究TR4靶基因硬脂酰辅酶A去饱和酶(SCD)1的调节作用。TR4的反式激活通过二甲双胍诱导的丝氨酸351位AMP激活的蛋白激酶(AMPK)的磷酸化而被抑制，从而导致SCD1基因表达的抑制。另一种机械解剖发现，Tr4反式激活的SCD1启动子活性是通过直接与启动子区域上位于−243到−255的Tr4反应元件结合来实现的。通过Tr4基因敲除小鼠和Tr4基因敲除或过表达的原代肝细胞，研究了二甲双胍→AMPK→Tr4SCD1scd1途径的病理生理学后果。结果表明，Tr4的缺失抑制了Scd1基因的表达，降低了脂肪质量，增加了胰岛素敏感性，增加了β氧化作用，降低了成脂基因表达。二甲双胍→-AMPK-→-Tr4-→-SCd1-→的胰岛素敏感性途径提示，Tr4可能是控制脂代谢的重要调节剂，这为利用小分子调节Tr4活性作为对抗代谢综合征的新途径提供了新的思路。
TR4 is a nuclear receptor without clear pathophysiological roles. We investigated the roles of hepatic TR4 in the regulation of lipogenesis and insulin sensitivity in vivo and in vitro. TR4 activity and phosphorylation assays were carried out using hepatocytes and various TR4 wild-type and mutant constructs. Liver tissues from TR4 knockout, C57BL/6, and db/db mice were examined to investigate TR4 target gene stearoyl-CoA desaturase (SCD) 1 regulation. TR4 transactivation is inhibited via phosphorylation by metformin-induced AMP-activated protein kinase (AMPK) at the amino acid serine 351, which results in the suppression of SCD1 gene expression. Additional mechanistic dissection finds TR4-transactivated SCD1 promoter activity via direct binding to the TR4-responsive element located at −243 to −255 on the promoter region. The pathophysiological consequences of the metformin→AMPK→TR4→SCD1 pathway are examined via TR4 knockout mice and primary hepatocytes with either knockdown or overexpression of TR4. The results show that the suppression of SCD1 via loss of TR4 resulted in reduced fat mass and increased insulin sensitivity with increased β-oxidation and decreased lipogenic gene expression. The pathway from metformin→AMPK→TR4→SCD1→insulin sensitivity suggests that TR4 may function as an important modulator to control lipid metabolism, which sheds light on the use of small molecules to modulate TR4 activity as a new alternative approach to battle the metabolic syndrome.
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影响因子：
7.7
作者：
Biddinger, SB;Almind, K;Kahn, CR
通讯作者：
Kahn, CR
DOI：
10.1124/jpet.105.093831
发表时间：
2006-02-01
影响因子：
3.5
作者：
Loffler, M;Bilban, M;Stulnig, TM
通讯作者：
Stulnig, TM
影响因子：
7.7
作者：
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通讯作者：
Vollenweider, Peter
DOI：
10.1097/01.mco.0000214564.59815.af
发表时间：
2006-03-01
影响因子：
3.1
作者：
Sampath, H;Ntambi, JM
通讯作者：
Ntambi, JM
影响因子：
7.7
作者：
Kim, Yong Deuk;Park, Keun-Gyu;Choi, Hueng-Sik
通讯作者：
Choi, Hueng-Sik