The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity
The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity
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DOI：
10.1194/jlr.m800520-jlr200
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发表时间：
2009-06-01
影响因子：
6.5
通讯作者：
Farese, Robert V.
中科院分区：
文献类型：
--
作者：
Sajan, Mini P.;Standaert, Mary L.;Farese, Robert V.
肥胖常与全身性胰岛素抵抗、葡萄糖耐受不良和高脂血症有关。肌肉中胰岛素作用受损和矛盾的饮食/胰岛素依赖的肝脏脂质过度产生是肥胖的重要组成部分，但其发病机制和肌肉与肝脏之间的相互关系尚不清楚。我们研究了两种小鼠肥胖模型，中度高脂肪喂养和杂合肌肉特异性PKC-lambda敲除，在这两种模型中，非典型蛋白激酶C （aPKC）的胰岛素激活在肌肉中受损，但在肝脏中保守。在这两种模型中，肝脏固醇受体元件结合蛋白1c （SREBP-1c）和NF κ B（核因子- κ B）的激活在喂养状态下长期升高，它们是肝脏脂质合成和全身胰岛素抵抗的主要调节因子。为了支持aPKC的重要调节作用，在两种模型中，通过腺病毒介导的激酶失活aPKC表达抑制肝aPKC，可显著降低饮食/胰岛素依赖型肝脏SREBP-1c和NF κ B的激活，并同时改善肝纤维化、高甘油三酯血症、高胰岛素血症和高血糖症。此外，在高脂肪喂养的小鼠中，肌肉和高胰岛素血症中irs -1依赖性磷脂酰肌醇3-激酶、PKB/Akt和aPKC的胰岛素信号受损在很大程度上得到逆转。在肥胖中，肝脏中SREBP-1c和NF κ B的依赖性活化对肝脏脂肪生成、高脂血症和全身性胰岛素抵抗的发展起着重要作用。因此，肝脏aPKC是治疗肥胖相关异常的潜在靶点。——萨扬，M. P.， M. L. Standaert， S. Nimal， U. Varanasi， T. Pastoor， S. Mastorides， U. Braun， M. Leitges， R. V. Farese非典型蛋白激酶C在肥胖中激活肝脏SREBP-1c和NF κ B的关键作用。[j] .油脂杂志。2009。: 1133 - 1145。
Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC-lambda knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NF kappa B (nuclear factor-kappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NF kappa B, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat-fed mice, impaired insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NF kappa B contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesity-associated abnormalities.-Sajan, M. P., M. L. Standaert, S. Nimal, U. Varanasi, T. Pastoor, S. Mastorides, U. Braun, M. Leitges, and R. V. Farese. The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NF kappa B in obesity. J. Lipid Res. 2009. 50: 1133-1145.