Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome
Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome
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DOI：
10.1016/j.hepres.2005.09.032
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发表时间：
2005-10-01
影响因子：
4.2
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Ueki, K;Kadowaki, T;Kahn, CR
胰岛素抵抗、肥胖、糖尿病、血脂异常和非酒精性脂肪肝是代谢综合征的组成部分，代谢综合征是一种在西方国家以流行率增加的疾病。虽然促炎性细胞因子已被认为有助于这些疾病的发展，但这种综合征发展的分子机制知之甚少。在这项研究中，我们发现，细胞因子信号转导抑制因子SOCS-1和SOCS-3在肥胖胰岛素抵抗动物的肝脏中的表达增加，并且腺病毒介导的SOCS-1或SOCS-3在肝脏中的过表达通过下调胰岛素受体底物（IRS）蛋白的酪氨酸磷酸化而引起胰岛素抵抗。此外，增加的SOCS-1和SOCS-3还导致肝脏中脂肪酸合成的关键调节因子固醇调节元件结合蛋白（SREBP）-1显著上调。相反，通过反义治疗抑制肥胖糖尿病dbldb小鼠肝脏中的SOCS-1和SOCS-3适度改善胰岛素敏感性，但使SREBP-1的表达增加完全正常化。后者导致肝脏脂肪变性和高甘油三酯血症的显著改善。启动子活性分析显示，SOCS-1或SOCS-3的表达，其中SOCS-3更有效地增强SREBP-1c的表达，而它被STAT 3的表达抑制。这种STAT 3介导的SREBP-1c表达的抑制被SOCS蛋白的共表达所拮抗。此外，db/db小鼠显示肝脏中STAT 3磷酸化降低，其通过SOCS蛋白的反义处理而正常化。这些数据表明，肥胖受试者在持续的炎症状态，如升高的循环肿瘤坏死因子-α，可能有下调STAT 3介导的信号通过增加SOCS蛋白，导致上调SREBP-1c的表达和增加脂肪酸合成在肝脏。因此，SOCS蛋白通过协调调节细胞因子信号和胰岛素信号在代谢综合征的发病机制中起重要作用。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
Insulin resistance, obesity, diabetes, dyslipidemia and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflaniniatory cytokines have been Suggested to contribute to the development of these disorders, the Molecular mechanism of the development of this syndrome is poorly understood. In this study, we show that expression of suppressor of cytokine signaling SOCS-1 and SOCS-3 is increased in livers of obese insulin-resistant animals, and that adenoviral-mediated overexpression of SOCS-1 or SOCS-3 in liver causes insulin resistance through down-regulation of tyrosine phosphorylation Of insulin receptor substrate (IRS) proteins. Moreover, the increased SOCS-1 and SOCS-3 also cause a prominent up-regulation of the key regulator of fatty acid synthesis in liver, sterol regulatory element binding protein (SREBP)-1. Conversely, inhibition of SOCS-1 and SOCS-3 in livers of obese diabetic dbldb mice by antisense treatment modestly improves insulin sensitivity, but completely normalizes the increased expression of SREBP-1. The latter leads to dramatic amelioration of hepatic steatosis and hypertriglyceridemia. Promoter activity analysis reveals that expression of SOCS-1 or SOCS-3 with SOCS-3 being more potent enhances SREBP-1c expression, while it is inhibited by expression of STAT3. This STAT3-mediated inhibition of SREBP-1c expression is antagonized by co-expression of SOCS proteins. Moreover, db/db mice display decreased STAT3 phosphorylation in liver that is normalized by antisense treatment of SOCS proteins. These data Suggest that obese Subjects in the persistent inflammatory states, Such as elevated circulating tumor necrosis factor-alpha, may have down-regulated STAT3-mediated signaling by increased SOCS proteins, leading to up-regulation of SREBP-1c expression and increased fatty acid synthesis in liver. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating cytokine signaling and insulin signaling. (c) 2005 Elsevier Ireland Ltd. All rights reserved.