Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
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DOI：
10.1016/j.cmet.2010.07.003
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发表时间：
2010-08-04
期刊：
影响因子：
29
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Li J;Romestaing C;Han X;Li Y;Hao X;Wu Y;Sun C;Liu X;Jefferson LS;Xiong J;Lanoue KF;Chang Z;Lynch CJ;Wang H;Shi Y
氧化应激通过未知的机制引起线粒体功能障碍和代谢并发症。心磷脂（CL）是氧化磷酸化所需的关键线粒体磷脂。病理性重塑对CL的氧化损伤与线粒体功能障碍的病因学有关，线粒体功能障碍通常与糖尿病、肥胖和其他代谢疾病相关。在这里，我们表明，ALCAT 1，氧化应激和饮食诱导的肥胖症（DIO）上调的溶血CL酰基转移酶，催化CL物种的合成，这些物种对氧化损伤高度敏感，导致线粒体功能障碍，ROS产生和胰岛素抵抗。这些代谢紊乱让人想起在2型糖尿病中观察到的代谢紊乱，并被罗格列酮治疗逆转。因此，ALCAT 1缺乏阻止了DIO的发生，并显着改善了ALCAT 1 −/−小鼠的线粒体复合物I活性，脂质氧化和胰岛素信号传导。总的来说，这些发现确定了ALCAT 1在调节CL重塑、线粒体功能障碍和DIO易感性中的关键作用。
Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here we show that ALCAT1, a lyso-CL acyltransferase up-regulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species which are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes, and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1−/− mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.
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