Bae Eun Ju, Yang Yoon Mee, Kim Jin Wan, Kim Sang Geon
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Hepatology. 2007 Sep;46(3):730-9. doi: 10.1002/hep.21769.
Several established liver diseases of various causes are highly associated with hepatic insulin resistance, which is characterized by the desensitization of target cells to insulin. Peripheral insulin resistance is observed in most patients who have cirrhosis. Conversely, insulin-resistant diabetic patients are at increased risk for developing liver disease. Current therapeutic interventions in insulin resistance are limited and therefore likely to be advanced by new tailor-made drugs. Oltipraz, a prototype dithiolthione, inhibits transforming growth factor beta1 and has the ability to regenerate cirrhotic liver. We investigated the effects of oltipraz and synthetic dithiolthiones on hepatic insulin resistance and the molecular basis of action. Oltipraz and other dithiolethione compounds were tested on tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance and glucose homeostasis in vitro and in vivo via immunoblotting, plasmid transfection, kinase analysis, and functional assays. Oltipraz treatment inhibited the ability of TNF-alpha to activate p70 ribosomal S6 kinase-1 (S6K1) downstream of mammalian target of rapamycin, thus preventing insulin receptor substrate-1 serine phosphorylation and protecting insulin signals. Moreover, oltipraz activated AMP-activated protein kinase (AMPK), whose inhibition by a dominant negative mutant abolished S6K1 inhibition and protected insulin signaling, indicating that AMPK activation leads to S6K1 inhibition. In hepatocyte-derived cell lines, oltipraz inhibited glucose production. Oltipraz prevented hepatic insulin resistance in C57BL/6 mice challenged with endotoxin (or TNF-alpha), leptin-deficient mice, and mice fed a high-fat diet. Synthetic dithiolethiones comparably inhibited insulin resistance.
Our findings led to the identification of dithiolethione compounds that prevent insulin resistance through a mechanism involving AMPK-mediated S6K1 inhibition and thereby sensitize hepatic insulin response.
多种病因所致的几种已确诊的肝脏疾病与肝脏胰岛素抵抗高度相关,其特征为靶细胞对胰岛素脱敏。大多数肝硬化患者存在外周胰岛素抵抗。相反,胰岛素抵抗的糖尿病患者发生肝脏疾病的风险增加。目前针对胰岛素抵抗的治疗干预措施有限,因此可能需要新型定制药物来推进治疗。奥替普拉是二硫硫酮的原型,可抑制转化生长因子β1,并具有使肝硬化肝脏再生的能力。我们研究了奥替普拉和合成二硫硫酮对肝脏胰岛素抵抗的影响及其作用的分子基础。通过免疫印迹、质粒转染、激酶分析和功能测定,在体外和体内测试了奥替普拉和其他二硫醇硫酮化合物对肿瘤坏死因子α(TNF-α)诱导的胰岛素抵抗和葡萄糖稳态的影响。奥替普拉治疗可抑制TNF-α激活雷帕霉素哺乳动物靶点下游的p70核糖体S6激酶-1(S6K1)的能力,从而防止胰岛素受体底物-1丝氨酸磷酸化并保护胰岛素信号。此外,奥替普拉激活了AMP激活的蛋白激酶(AMPK),其被显性负突变体抑制可消除S6K1抑制并保护胰岛素信号,表明AMPK激活导致S6K1抑制。在肝细胞系中,奥替普拉抑制葡萄糖生成。奥替普拉可预防用内毒素(或TNF-α)攻击的C57BL/6小鼠、瘦素缺乏小鼠和高脂饮食喂养小鼠的肝脏胰岛素抵抗。合成二硫醇硫酮同样抑制胰岛素抵抗。
我们的研究结果导致鉴定出二硫醇硫酮化合物,其通过涉及AMPK介导的S6K1抑制的机制预防胰岛素抵抗,从而使肝脏胰岛素反应敏感化。