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

项目概要/摘要 据估计，非酒精性脂肪肝（NAFLD）发生在三分之一的普通人群中，是一种常见的肝病。 肝脏胰岛素抵抗和2型糖尿病（T2 D）发病机制中的主要诱发因素。NAFLD 当肝脏的脂质供应超过脂质氧化和脂质输出的速率时发生。一些治疗方法 已被用于减少异位脂质积累和肝脏胰岛素抵抗，然而，这些 这些方法在长期内取得的成功有限，因此需要新的药物。乙酰-coa 羧化酶（ACC）同工酶ACC 1和ACC 2催化丙二酰辅酶A的合成，丙二酰辅酶A是脂肪酸的前体。 酸合成和脂肪酸氧化的肉毒碱/棕榈酰穿梭系统的变构抑制剂。给定 由于ACC在中间代谢中的独特地位，药物抑制ACC提供了一种有吸引力的治疗方法， 同时抑制脂肪酸合成和刺激脂肪酸氧化， 肥胖、糖尿病和脂肪肝。在这方面，我们的实验室先前已经证明， 利昔单抗介导的肝ACC 1和ACC 2抑制可导致 高脂喂养大鼠高甘油三酯血症、肝脏甘油三酯含量和肝脏胰岛素抵抗逆转 NAFLD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， ACC 1和ACC 2（GS-834356）对饮食诱导的大鼠模型中肝脂肪变性和肝胰岛素抵抗的影响 肥胖此外，我们将进行一系列全面的肝脏代谢通量测量，以评估 肝线粒体氧化率、回补率、生酮率和肝新生 脂肪生成（DNL）。我们假设GS-834356对肝脏ACC的慢性抑制将导致 肝脂肪含量，由于肝线粒体氧化增加和DNL减少，这反过来又会 导致肝胰岛素敏感性增加。[我们实验室最近的初步数据也表明， GS-834356对肝ACC的慢性抑制矛盾地驱动高胆固醇血症。因此，我们也 旨在阐明这种情况发生的分子机制。总的来说，这项研究的结果 将提供有价值的见解，在代谢作用的肝脏特异性抑制ACC，这将提高我们的研究。 了解基础脂质生物学，并可能导致药理学的发展/改进 治疗NAFLD和T2 D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.]