Effects of Hepatic Acetyl-CoA Carboxylase Inhibition on NAFLD and Hepatic Insulin Resistance

肝乙酰辅酶 A 羧化酶抑制对 NAFLD 和肝胰岛素抵抗的影响

• 批准号: 9361162
• 负责人: GERALD I SHULMAN
• 金额: $ 73.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9361162
• 关键词: Acetyl-CoA Carboxylase; Adipocytes; Adipose tissue; Affect; Alcoholic Liver Cirrhosis; Animal Model; Antisense Oligonucleotides; Chronic; Cirrhosis; Citrate (si)-Synthase; Data; Development; Diabetes Mellitus; Disease; Double-Blind Method; Energy Metabolism; Enzymes; Euglycemic Clamping; Fatty Liver; Fatty acid glycerol esters; General Population; Gluconeogenesis; Glucose; Glycerol; Grant; Hepatic; Hepatitis C; Human; Hypertriglyceridemia; Indirect Calorimetry; Insulin; Insulin Resistance; Lipids; Liver; Magnetic Resonance Spectroscopy; Mediating; Methods; Mitochondria; Modeling; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Non-Rodent Model; Palmitates; Phase; Phase II Clinical Trials; Placebo Control; Predisposing Factor; Primary carcinoma of the liver cells; Pyruvate Carboxylase; Randomized; Rattus; Skeletal Muscle; Testing; Tracer; Translating; Triglycerides; beta-Hydroxybutyrate; fatty acid oxidation; global health; glucose metabolism; glucose production; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; ketogenesis; lipid biosynthesis; lipid metabolism; liver transplantation; new therapeutic target; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; oxidation; respiratory; small molecule inhibitor

Non alcoholic fatty liver disease (NAFLD) is estimated to affect up to one third of the general population and there is a strong relationship between NAFLD, hepatic insulin resistance and type 2 diabetes (T2D). NAFLD is also a key predisposing factor for the development of non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma and it is anticipated that NAFLD-induced NASH will soon surpass hepatitis C and alcoholic cirrhosis as the most common indication for liver transplantation in the USA. Therefore there is a great unmet need for new drugs that are effective at reducing hepatic steatosis and hepatic insulin resistance. In this grant we will examine the chronic effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA carboxylase on hepatic triglyceride content as well as hepatic glucose and lipid metabolism in NAFLD subjects in a randomized double-blinded placebo-controlled parallel group study. Specifically we will examine the chronic (21 days) effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA carboxylase on: 1) Hepatic triglyceride content assessed by 1H magnetic resonance spectroscopy (MRS), 2) Hepatic, skeletal muscle and adipocyte insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp in conjunction with [6,6-2H2]glucose, [2H5]glycerol, and [13C16]palmitate turnover, 3) Rates of hepatic mitochondrial oxidation directly assessed by in vivo 13C magnetic resonance spectroscopy, 4) Rates of hepatic ketogenesis assessed by [13C4]β-hydroxybutyrate turnover, 5) Hepatic de novo lipogenesis (DNL) and gluconeogenesis assessed by 2H2O, 6) Relative flux rates of hepatic pyruvate carboxylase flux (VPC)/citrate synthase flux (VCS) assessed by a novel Positional Isotopomer NMR Tracer Analysis (PINTA) method and 7) Whole body energy expenditure, VO2, VCO2, respiratory quotient assessed by indirect calorimetry. We hypothesize that chronic inhibition of acetyl-CoA carboxylase will result in decreased hepatic steatosis due to increased hepatic mitochondrial fat oxidation and decreased DNL. We also anticipate that this reduction in hepatic steatosis will be associated with improved hepatic insulin sensitivity as reflected by increased suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The results of these studies will provide important new proof of concept data in support of liver-targeted acetyl CoA carboxylase inhibition as a therapy for NAFLD and T2D as well as fundamental new insights into the mechanisms by which liver-targeted acetyl CoA carboxylase inhibition reduces hepatic steatosis, decreases hepatic insulin resistance and alters hepatic mitochondrial fat oxidation. !

据估计，非酒精性脂肪肝（NAFLD）影响多达三分之一的普通人群， 在NAFLD、肝脏胰岛素抵抗和2型糖尿病（T2 D）之间存在强相关性。NAFLD是 也是非酒精性脂肪性肝炎（NASH）、肝硬化和 肝细胞癌，预计NAFLD诱导的NASH将很快超过丙型肝炎， 酒精性肝硬化是美国最常见的肝移植指征。因此有 对有效减少肝脂肪变性和肝胰岛素抵抗的新药的巨大未满足的需求。 在这项资助中，我们将研究一种新型的肝脏靶向乙酰辅酶A小分子抑制剂的慢性效应 羧化酶对非酒精性脂肪性肝病患者肝脏甘油三酯含量及肝脏糖脂代谢的影响 在一项随机双盲安慰剂对照平行组研究中。具体来说，我们将研究 乙酰辅酶A羧化酶的新型肝靶向小分子抑制剂的慢性（21天）作用：1） 通过1H磁共振波谱（MRS）评估肝脏甘油三酯含量，2）肝脏、骨骼 通过高胰岛素-正葡萄糖钳夹结合 [6，6 - 2 H2]葡萄糖、[2 H5]甘油和[13 C16]棕榈酸转换，3）肝线粒体氧化速率 通过体内13 C磁共振波谱直接评估，4）评估肝生酮速率 通过[13 C4]β-羟基丁酸转换，5）通过评估肝脏从头脂肪生成（DNL）和糖异生 6）通过以下方法评估的肝丙酮酸羧化酶通量（VPC）/柠檬酸合酶通量（VPC）的相对通量率： 新的位置同位素NMR示踪剂分析（PINTA）方法和7）全身能量消耗， 通过间接量热法评估VO 2、VCO 2、呼吸商。我们假设， 乙酰辅酶A羧化酶将由于肝线粒体脂肪增加而导致肝脂肪变性减少 氧化和降低DNL。我们还预计肝脏脂肪变性的减少将与 改善肝脏胰岛素敏感性，反映为在治疗期间增加对肝脏葡萄糖产生的抑制 一种高胰岛素-正葡萄糖钳夹。这些研究的结果将提供重要的新概念证明 支持肝脏靶向乙酰辅酶A羧化酶抑制作为NAFLD和T2 D治疗的数据，以及 肝脏靶向乙酰辅酶A羧化酶抑制机制的基本新见解 减少肝脂肪变性、降低肝胰岛素抵抗和改变肝线粒体脂肪氧化。 !