Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C
Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C
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DOI：
10.1016/j.jhep.2010.06.021
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发表时间：
2011-01-01
影响因子：
25.7
通讯作者：
Martin-Sanz, Paloma
中科院分区：
文献类型：
--
作者：
Garcia-Monzon, Carmelo;Lo Iacono, Oreste;Martin-Sanz, Paloma
背景和目标：我们的目的是阐明是否肝胰岛素抵抗可能有助于肝细胞凋亡和纤维化的非酒精性脂肪性肝病（NAFLD）和慢性丙型肝炎病毒（HCV）infection.Methods：27非酒精性脂肪变性（NAST），24非酒精性脂肪性肝炎（NASH），71 HCV，和29例组织学正常的肝脏（NL）患者进行了研究。实时PCR，TUNEL法，和Western印迹被用来评估胰岛素信号分子，肝细胞凋亡，抗凋亡介质，活性半胱天冬酶3，和I型胶原在肝活检。使用HCV核心转染的人肝细胞作为体外模型。结果：在NAFLD患者中，肝脏胰岛素受体底物（IRS）1、IRS 2 2、磷脂酰肌醇3-激酶的p85 α亚基（p85 α）、磷酸化蛋白激酶B（pAkt）、含磷酸化叉头盒蛋白O亚家族-1（FoxO）、NASH组的5'腺苷一磷酸活化蛋白激酶（pAMPK）、抗凋亡介质B细胞淋巴瘤2蛋白（Bcl-2）和髓细胞白血病蛋白1（Mcl-1）的表达均显著低于NAST和NL组。此外，肝细胞凋亡和增加的活性caspase 3只存在于NASH。在HCV患者中，肝脏胰岛素信号明显受损，无论病毒基因型和脂肪变性伴细胞凋亡增强。在培养的人肝细胞中，HCV核心蛋白降低pAkt并增加c-Jun N-末端激酶（INK）的磷酸化。这种效果在脂质负载hepatocyte.Conclusions：肝脏胰岛素信号在NASH和HCV患者受损，下调胰岛素敏感性靶点与这两种情况下的细胞凋亡和纤维化增加有关。JNK可能是HCV诱导胰岛素抵抗的靶点。(C)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: We aimed to elucidate whether hepatic insulin resistance may contribute to hepatocyte apoptosis and fibrogenesis in nonalcoholic fatty liver disease (NAFLD) and in chronic hepatitis C virus (HCV) infection.Methods: Twenty-seven nonalcoholic steatosis (NAST), 24 nonalcoholic steatohepatitis (NASH), 71 HCV, and 29 patients with histological normal liver (NL) were studied. Real-time PCR, the TUNEL assay, and Western blots were used to assess insulin-signaling molecules, hepatocyte apoptosis, antiapoptotic mediators, active caspase 3, and type I collagen in liver biopsies. HCV core-transfected human hepatocytes were used as an in vitro model.Results: In NAFLD patients, hepatic levels of insulin receptor substrate (IRS) 1, IRS2 2, the p85 alpha subunit of phosphatidylinositol 3-kinase (p85 alpha), phosphorylated protein kinase B (pAkt), phosphorylated forkhead box-containing protein O subfamily-1 (FoxO), and phosphorylated 5' adenosine monophosphate-activated protein kinase (pAMPK) as well as the antiapoptotic mediators B-cell lymphoma 2 protein (Bcl-2) and myeloid cell leukemia protein-1 (Mcl-1) were significantly lower in NASH than in NAST and NL. Furthermore, hepatocyte apoptosis and increased active caspase 3 were only present in NASH. In HCV patients, hepatic insulin signaling was markedly impaired, regardless of viral genotype and the presence of steatosis paralleled with enhanced apoptosis. In cultured human hepatocytes, HCV core protein decreased pAkt and increased phosphorylation of c-Jun N-terminal kinase (INK). This effect was more pronounced in lipid-loaded hepatocytes.Conclusions: Hepatic insulin signaling is impaired in NASH and HCV patients, and downregulation of insulin-sensitive targets is associated with increased apoptosis and fibrogenesis in both conditions. JNK might be a target for HCV-induced insulin resistance. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.