Effect of Liver-Specific Acetyl-CoA Carboxylase Inhibition on Hepatic Steatosis and Insulin Resistance

项目摘要/摘要 非酒精性脂肪性肝病(NAFLD)估计发生在三分之一的普通人群中，是一种 肝脏胰岛素抵抗和2型糖尿病(T2D)发病的主要易感因素。NAFLD 当肝脏的脂质供应超过脂质氧化和脂类输出的速率时发生。一些治疗方法 已经被用来减少异位脂肪堆积和肝脏胰岛素抵抗，然而这些 从长远来看，这些方法取得的成功有限，需要新的药物。乙酰辅酶A 羧基酶(ACC)同工酶ACC1和ACC2催化脂肪前体丙二酰辅酶A的合成 用于脂肪酸氧化的肉碱/棕榈酰穿梭系统的酸合成和变构抑制剂。vt.给出 它在中间代谢中的独特地位，对ACC的药理学抑制为治疗提供了一种诱人的治疗方法 同时抑制脂肪酸合成和刺激脂肪酸氧化，治疗效果良好 肥胖、糖尿病和脂肪肝。在这方面，我们的实验室之前已经证明了反义 寡核苷酸介导的对肝脏ACC1和ACC2的抑制导致显著减少 高脂饲料大鼠高甘油三酯血症、肝脏甘油三酯含量与肝脏胰岛素抵抗的逆转 非酒精性脂肪肝的啮齿动物模型。在这里，我们将评估一种新的肝特异性小分子抑制剂的影响。 Acc1和Acc2(GS-834356)对饮食诱导的大鼠肝脏脂肪变性和肝脏胰岛素抵抗的影响 肥胖。此外，我们将进行一套全面的肝脏代谢流量测量，以评估 肝脏线粒体氧化率、停滞率、酮体生成率和肝脏新生 脂肪生成(DNL)。我们假设GS-834356对肝脏ACC的慢性抑制将导致 肝脏脂肪含量，由于肝脏线粒体氧化增加和DNL减少，这反过来将 导致肝脏对胰岛素的敏感性增加。[我们实验室最近的初步数据也证明了 GS-834356对肝脏ACC的慢性抑制反常地导致高甘油三酯血症。因此，我们也 目的阐明这种现象发生的分子机制。总而言之，这项研究的结果 将为肝脏特异性抑制ACC的代谢影响提供有价值的见解，这将改善我们的 了解基本的脂类生物学，并可能导致药理学的发展/改进 治疗NAFLD和T2D的方法。]

PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is estimated to occur in one third of the general population and is a major predisposing factor in the pathogenesis of hepatic insulin resistance and type 2 diabetes (T2D). NAFLD occurs when lipid supply to the liver exceeds rates of lipid oxidation and lipid export. A number of therapies have been employed to reduce ectopic-lipid accumulation and hepatic insulin resistance, however these approaches have been met with limited success in the long-term and new drugs are required. The acetyl-CoA carboxylase (ACC) isoenzymes, ACC1 and ACC2, catalyze the synthesis of malonyl-coA, a precursor for fatty acid synthesis and an allosteric inhibitor of the carnitine/palmitoyl shuttle system for fatty acid oxidation. Given its unique position in intermediary metabolism, pharmalogic inhibition of ACC offers an attractive therapy to simultaneously inhibit fatty acid synthesis and stimulate fatty acid oxidation, favorable outcomes in treating obesity, diabetes and fatty liver disease. In this regard, our lab has previously demonstrated that antisense oligonucleotide-mediated inhibition of hepatic ACC1 and ACC2 results in marked reductions in hypertriglyceridemia, hepatic triglyceride content and reversal of hepatic insulin resistance in a high fat-fed rodent model of NAFLD. Here, we will evaluate the impact of a novel hepatospecific small molecule inhibitor of ACC1 and ACC2 (GS-834356) on hepatic steatosis and hepatic insulin resistance in rat models of diet-induced obesity. In addition, we will perform a comprehensive set of hepatic metabolic flux measurements to assess rates of hepatic mitochondrial oxidation, rates of anaplerosis, rates of ketogenesis, and hepatic de novo lipogenesis (DNL). We hypothesize that chronic inhibition of hepatic ACC by GS-834356 will lead to reduced hepatic fat content, due to increases in hepatic mitochondrial oxidation and reduced DNL, which in turn will lead to increased hepatic insulin sensitivity. [Recent preliminary data from our lab has also demonstrated that chronic inhibition of hepatic ACC by GS-834356 paradoxically drives hypertriglyceridemia. As such, we also aim to elucidate the molecular mechanism by which this is occurring. Collectively, the results of this research will provide valuable insight in the metabolic effects of liver-specific inhibition of ACC, which will improve our understanding of basic lipid biology and may lead to the development/improvement of pharmacologic approaches for treating NAFLD and T2D.]