Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance
Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance
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肝脏 DsbA-L 保护小鼠免受饮食诱导的肝脂肪变性和胰岛素抵抗
DOI：
10.1096/fj.201600985r
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Feng
中科院分区：
文献类型：
--
作者：
Chen, Hongzhi;Bai, Juli;Liu, Feng
饮食诱导肥胖的肝脏胰岛素抵抗和脂肪肝与多种代谢性疾病有关，但其潜在机制仍有待充分阐明。在这里，我们表明，二硫键A氧化还原酶样蛋白（DsbA-L）的表达水平显着降低在肥胖小鼠和人类的肝脏。肝脏特异性敲除或腺病毒介导的DsbA-L加剧剂或DsbA-L抑制剂的过度表达分别导致高脂饮食诱导的小鼠线粒体功能障碍、脂肪肝和胰岛素抵抗。从机制上讲，我们发现DsbA-L定位于线粒体中，其缺乏与最大呼吸能力受损、细胞氧化应激升高和JNK活性增加有关。我们的研究结果确定DsbA-Las是线粒体功能的关键调节因子，其在肝脏中的下调可能有助于肥胖诱导的脂肪肝和全身胰岛素抵抗。
Hepatic insulin resistance and hepatosteatosis in diet-induced obesity are associated with various metabolic diseases, yet the underlying mechanisms remain to be fully elucidated. Here we show that the expression levels of the disulfide-bond A oxidoreductase-like protein (DsbA-L) are significantly reduced in the liver of obese mice and humans. Liver-specific knockout or adenovirus-mediated overexpression of DsbA-Lexacerbates or alleviates, respectively, high-fat diet-induced mitochondrial dysfunction, hepatosteatosis, and insulin resistance in mice. Mechanistically, we found that DsbA-L is localized in mitochondria and that its deficiency is associated with impairment of maximum respiratory capacity, elevated cellular oxidative stress, and increased JNK activity. Our results identify DsbA-Las a critical regulator of mitochondrial function, and its down-regulation in the liver may contribute to obesity-induced hepatosteatosis and whole body insulin resistance.