Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis
Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis
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DOI：
10.1074/jbc.m210208200
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发表时间：
2003-01-10
影响因子：
4.8
通讯作者：
Etgen, GJ
中科院分区：
文献类型：
--
作者：
Cao, GQ;Liang, Y;Etgen, GJ
氧化固醇受体LXR（肝脏X受体）-α和LXR β是在胆固醇和脂肪酸代谢的调节中起关键作用的核受体。我们发现LXR在葡萄糖代谢中也起着重要作用。用LXR激动剂T0901317治疗糖尿病啮齿动物导致血糖显著降低。在胰岛素抵抗Zucker（fa/fa）大鼠中，T0901317显著改善了胰岛素敏感性。LXR的激活并不诱导强大的脂肪生成，而是抑制了参与肝脏脂肪生成的几个基因的表达，包括磷酸烯醇式丙酮酸羧激酶（PEPCK）。由于这种调节，肝脏葡萄糖输出显著减少。核运行的研究表明，转录抑制是主要负责抑制PEPCK的LXR激动剂。此外，我们还发现LXR激动剂对肝细胞致凋亡途径的调节是对肝细胞的直接影响。这些数据不仅表明LXR是糖尿病的新靶点，而且还揭示了这些受体的意想不到的作用，进一步将脂质和葡萄糖代谢联系起来。
The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.