Foxo1 integrates insulin signaling with mitochondrial function in the liver.
Foxo1 integrates insulin signaling with mitochondrial function in the liver.
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作者：
2型糖尿病是一种以糖脂代谢紊乱为特征的复杂疾病。肝脏胰岛素抵抗在2型糖尿病中尤其严重，因为它会紊乱空腹和餐后糖耐量，并促进全身性血脂异常和非酒精性脂肪性肝病。线粒体功能障碍与胰岛素抵抗密切相关，并可能导致糖尿病的进展。在这里，我们使用先前产生的由于编码胰岛素受体底物-1(IRS-1)和IRS-2的基因缺失而产生的肝脏胰岛素抵抗的小鼠(这里称为双基因敲除(DKO)小鼠)来建立调节失调的胰岛素作用与线粒体功能之间的分子联系。几个叉头盒O1(Foxo1)靶基因在DKO肝脏中的表达增加，包括血红素加氧酶-1(Hmox1)，它破坏呼吸链的复合体III和IV，降低NAD+/NADH比率和ATP产生。尽管Ppargc-1α(Ppargc-1α)在DKO肝脏中也表达上调，但其乙酰化并不能促进线粒体的代偿性生物发生或功能。DKO肝组织中Foxo1的缺失可使Hmox1的表达和NAD+/NADH比值恢复正常，降低Ppargc-1α乙酰化水平，恢复线粒体氧化代谢和生物发生。因此，Foxo1整合了胰岛素信号和线粒体功能，抑制Foxo1可以改善胰岛素抵抗和代谢综合征期间的肝脏代谢。
Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes. Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD+/NADH ratio and ATP production. Although peroxisome proliferator–activated receptor-γ coactivator-1α (Ppargc-1α) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD+/NADH ratio, reduced Ppargc-1α acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.
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影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
64.8
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
通讯作者：
Montminy, Marc
影响因子：
7.7
作者：
Hwang JH;Kim DW;Jo EJ;Kim YK;Jo YS;Park JH;Yoo SK;Park MK;Kwak TH;Kho YL;Han J;Choi HS;Lee SH;Kim JM;Lee I;Kyung T;Jang C;Chung J;Kweon GR;Shong M
通讯作者：
Shong M
DOI：
10.1073/pnas.0702509104
发表时间：
2007-07-31
影响因子：
11.1
作者：
Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
64.8
作者：
Baur, Joseph A.;Pearson, Kevin J.;Sinclair, David A.
通讯作者：
Sinclair, David A.