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

基本信息

批准号：
9763549
负责人：
GERALD I SHULMAN
金额：
$ 72.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9763549
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 Fatty Liver Fatty acid glycerol esters General Population Gluconeogenesis Glucose Glucose Clamp Glycerol Grant Hepatic Hepatitis C Human Hypertriglyceridemia Indirect Calorimetry Insulin Insulin Resistance Lipids Liver Liver Mitochondria Magnetic Resonance Spectroscopy Mediating Methods Modeling Muscle Non-Insulin-Dependent Diabetes Mellitus Non-Rodent Model Palmitates Phase Phase II Clinical Trials Placebos 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 disease nonalcoholic steatohepatitis nondrug therapy novel novel therapeutics oxidation respiratory small molecule inhibitor

项目摘要

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，非酒精性脂肪性肝病 (NAFLD) 影响着多达三分之一的总人口， NAFLD、肝脏胰岛素抵抗和 2 型糖尿病 (T2D) 之间存在密切关系。也是发生非酒精性脂肪性肝炎 (NASH)、肝硬化和肝细胞癌，预计 NAFLD 引起的 NASH 将很快超过丙型肝炎和在美国，酒精性肝硬化是肝移植最常见的适应症。对有效减少肝脂肪变性和肝胰岛素抵抗的新药的巨大需求尚未得到满足。在这笔资助中，我们将研究一种新型肝脏靶向乙酰辅酶A小分子抑制剂的慢性影响羧化酶对 NAFLD 受试者肝脏甘油三酯含量以及肝脏葡萄糖和脂质代谢的影响具体来说，我们将在一项随机双盲安慰剂对照平行组研究中进行检查。新型肝脏靶向小分子乙酰辅酶A羧化酶抑制剂的慢性（21天）影响：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-正常血糖钳夹评估肌肉和脂肪细胞的胰岛素敏感性 [6,6-2H2]葡萄糖、[2H5]甘油和[13C16]棕榈酸酯周转率，3) 肝线粒体氧化率通过体内 13C 磁共振波谱直接评估，4) 评估肝生酮率通过 [13C4]β-羟基丁酸周转率，5) 通过评估肝脏从头脂肪生成 (DNL) 和糖异生 2H2O, 6) 肝脏丙酮酸羧化酶通量 (VPC)/柠檬酸合成酶通量 (VCS) 的相对通量率新颖的位置同位素核磁共振示踪分析 (PINTA) 方法和 7) 全身能量消耗，通过间接量热法评估 VO2、VCO2、呼吸商我们捕捉到了慢性抑制。由于肝线粒体脂肪增加，乙酰辅酶A羧化酶将导致肝脂肪变性减少我们还预计，这种肝脂肪变性的减少将与氧化和 DNL 减少有关。肝脏胰岛素敏感性的改善反映在肝葡萄糖产生的抑制增加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 T2D 以及 T2D 治疗的数据对肝脏靶向乙酰辅酶A羧化酶抑制机制的基本新见解减少肝脏脂肪变性，降低肝脏胰岛素抵抗并改变肝脏线粒体脂肪氧化。！