Cheng Zhiyong, Guo Shaodong, Copps Kyle, Dong Xiaochen, Kollipara Ramya, Rodgers Joseph T, Depinho Ronald A, Puigserver Pere, White Morris F
Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2009 Nov;15(11):1307-11. doi: 10.1038/nm.2049. Epub 2009 Oct 18.
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-gamma coactivator-1alpha (Ppargc-1alpha) 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-1alpha 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.
2型糖尿病是一种复杂的疾病，其特征为葡萄糖和脂质代谢功能障碍。肝脏胰岛素抵抗在2型糖尿病中尤其具有致病性，因为它会破坏空腹和餐后葡萄糖耐量，并促进全身性血脂异常和非酒精性脂肪肝病。线粒体功能障碍与胰岛素抵抗密切相关，可能会促进糖尿病的进展。在这里，我们使用先前生成的由于编码胰岛素受体底物-1（Irs-1）和Irs-2的基因缺失而具有肝脏胰岛素抵抗的小鼠（在此称为双敲除（DKO）小鼠）来建立胰岛素作用失调与线粒体功能之间的分子联系。几种叉头框O1（Foxo1）靶基因的表达在DKO肝脏中增加，包括血红素加氧酶-1（Hmox1），它会破坏呼吸链的复合物III和IV，并降低NAD(+)/NADH比率和ATP生成。尽管过氧化物酶体增殖物激活受体γ共激活因子-1α（Ppargc-1α）在DKO肝脏中也上调，但它被乙酰化，无法促进代偿性线粒体生物发生或功能。在DKO肝脏中删除肝脏Foxo1可使Hmox1的表达和NAD(+)/NADH比率正常化，降低Ppargc-1α的乙酰化，并恢复线粒体氧化代谢和生物发生。因此，Foxo1将胰岛素信号与线粒体功能整合在一起，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。
