Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism.
Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism.
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DOI：
10.1172/jci23187
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发表时间：
2005-03
期刊：
影响因子：
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通讯作者：
C. Taniguchi;K. Ueki;R. Kahn
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文献类型：
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作者：
C. Taniguchi;K. Ueki;R. Kahn
肝脏胰岛素抵抗是2型糖尿病发生发展的关键因素。在许多情况下，肝脏中的胰岛素抵抗与两种主要胰岛素受体底物（IRS）蛋白IRS-1和IRS-2的表达减少有关。为了研究IRS-1和IRS-2在体内调节肝功能的特异性功能，我们开发了一种腺病毒介导的RNA干扰技术，其中短发夹RNA（shRNAs）用于在WT小鼠肝脏中敲低IRS-1、IRS-2或两者，敲低70-80%。IRS-1的敲低导致促凋亡酶葡萄糖-6磷酸酶和磷酸烯醇丙酮酸羧激酶的上调，以及肝核因子-4 α的显著增加。IRS-1的降低也与葡萄糖激酶表达的降低和血糖升高的趋势相关，而IRS-2的敲低导致脂肪生成酶SREBP-1c和脂肪酸合成酶的上调，以及肝脏脂质蓄积的增加。同时注射IRS-1和IRS-2腺病毒shRNA导致全身性胰岛素抵抗、葡萄糖耐受不良和肝脂肪变性。双基因敲除小鼠的改变与Akt激活和Foxo 1磷酸化缺陷有关。总之，我们的研究结果表明，肝脏IRS-1和IRS-2在控制肝脏代谢中具有互补作用，IRS-1与葡萄糖稳态更密切相关，IRS-2与脂质代谢更密切相关。
Hepatic insulin resistance is a critical component in the development of type 2 diabetes mellitus. In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. The alterations in the dual-knockdown mice were associated with defective Akt activation and Foxo1 phosphorylation. Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism.