Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice
Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice
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DOI：
10.2337/db06-0200
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发表时间：
2006-08-01
期刊：
影响因子：
7.7
通讯作者：
Postic, Catherine
中科院分区：
文献类型：
--
作者：
Dentin, Renaud;Benhamed, Fadila;Postic, Catherine
肥胖是一种代谢紊乱，通常与2型糖尿病、胰岛素抵抗和肝脂肪变性相关。瘦素缺陷（ob/ob）小鼠是一种特征良好的肥胖小鼠模型，其中肝脏脂肪生成增加被认为是胰岛素抵抗表型的原因。我们最近已经证明，碳水化合物反应元件结合蛋白（ChREBP）通过脂肪生成基因的转录调控，包括乙酰辅酶A羧化酶和脂肪酸合成酶，在控制脂肪生成中起着关键作用。结果表明，ob/ob小鼠肝脏中ChREBP基因表达和ChREBP核蛋白含量显著增加。为了探讨ChREBP参与肝脂肪变性和胰岛素抵抗的病理生理学过程，我们开发了一种腺病毒介导的RNA干扰技术，利用短发夹RNA（shRNAs）抑制ChREBP在体内的表达。肝脏特异性抑制ChREBP在ob/ob小鼠中通过特异性降低脂肪生成率显著改善肝脂肪变性。肝脏脂肪变性的纠正也导致血浆甘油三酯和非酯化脂肪酸水平降低。因此，在用表达针对ChREBP的shRNA的重组腺病毒治疗7天后，ob/ob小鼠的肝脏、骨骼肌和白色脂肪组织中的胰岛素信号传导得到改善，并且总体葡萄糖耐量和胰岛素敏感性得到恢复。两者合计，我们的研究结果表明，ChREBP是中央的脂肪生成在体内的调节，并发挥了决定性的作用，在ob/ob小鼠的肝脂肪变性和胰岛素抵抗的发展。
Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient (ob/ob) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element-binding protein (ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetylCoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice.