Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler.
Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler.
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DOI：
10.1016/j.cmet.2013.10.004
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发表时间：
2013-11-05
期刊：
影响因子：
29
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Perry RJ;Kim T;Zhang XM;Lee HY;Pesta D;Popov VB;Zhang D;Rahimi Y;Jurczak MJ;Cline GW;Spiegel DA;Shulman GI
非酒精性脂肪肝 (NAFLD) 影响三分之一的美国人，是 2 型糖尿病 (T2D) 的主要诱发因素，但目前尚无药物可用于治疗这种疾病。我们研究了 2,4-二硝基苯酚 (DNP) 的功能性肝脏靶向衍生物 DNP-甲基醚 (DNPME) 是否可以安全地降低高甘油三酯血症、NAFLD 和胰岛素抵抗，而不会产生全身毒性。 DNPME 治疗可逆转高脂肪喂养大鼠的高甘油三酯血症、脂肪肝和全身胰岛素抵抗，并降低 T2D 大鼠模型的高血糖，具有广泛的治疗指数。肝脏和肌肉胰岛素抵抗的逆转与组织二酰甘油含量的降低以及肝脏和肌肉中 PKCε 和 PKCθ 活性的降低分别相关。这些结果表明，DNP 对高甘油三酯血症、脂肪肝和胰岛素抵抗的有益作用可以与全身毒性无关，并表明肝脏靶向线粒体解偶联剂在治疗 NAFLD、代谢综合征和 2 型糖尿病的相关流行病方面具有潜在用途。
Non-alcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for type 2 diabetes (T2D), however there are currently no drugs available to treat this disease. We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver and whole-body insulin resistance in high-fat fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in PKCε and PKCθ activity in liver and muscle respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of the related epidemics of NAFLD, metabolic syndrome and type 2 diabetes.
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影响因子：
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