Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver
Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver
复制标题
DOI：
10.1194/jlr.m023382
复制
发表时间：
2012-06-01
影响因子：
6.5
通讯作者：
Burgess, Shawn C.
中科院分区：
文献类型：
--
作者：
Satapati, Santhosh;Sunny, Nishanth E.;Burgess, Shawn C.
胰岛素抵抗影响肝线粒体功能的方式是复杂的。尽管肝脏胰岛素抵抗与呼吸功能障碍有关，但对脂肪氧化的影响仍存在争议，并且穿越线粒体的生物合成途径实际上增加了。三羧酸（TCA）循环是终端脂肪氧化的场所，呼吸电子的主要来源，糖异生的代谢祖细胞。因此，我们使用标准的生物分子和体内H-2/C-13示踪剂方法测试了胰岛素抵抗是否会促进高脂肪饮食（HFD） 32周进展为胰岛素抵抗和脂肪肝的小鼠肝脏TCA循环通量。线粒体相对含量升高，呼吸效率下降。空腹生酮对喂食或胰岛素钳无反应，表明线粒体β -氧化迟钝但构成活跃。胰岛素信号传导受损的标志是体内糖异生、倒转和氧化TCA循环通量升高。TCA循环功能的诱导与线粒体呼吸功能障碍、肝脏氧化应激和炎症的发生相对应。因此，肝脏TCA循环似乎通过增加电子沉积到容易产生活性氧的低效率呼吸链中，并通过提供线粒体来源的底物来提高糖异生，从而使胰岛素抵抗期间的线粒体功能障碍。-萨塔帕提，S. N. E.桑尼，B.库切约娃，傅新，何t.t.， A.门德斯-卢卡斯，J. M.谢尔顿，J. C.佩拉莱斯，J. D.布朗宁，S. C.伯吉斯。TCA循环功能升高在饮食性肝胰岛素抵抗和脂肪肝病理中的作用。[j] .油脂杂志。2012。53: 1080 - 1092。
The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo H-2/C-13 tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial beta-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.-Satapati, S., N. E. Sunny, B. Kucejova, X. Fu, T. T. He, A. Mendez-Lucas, J. M. Shelton, J. C. Perales, J. D. Browning, and S. C. Burgess. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J. Lipid Res. 2012. 53: 1080-1092.