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，非酒精脂肪肝病（NAFLD）会影响多达三分之一的普通人群和 NAFLD，肝胰岛素抵抗与2型糖尿病（T2D）之间存在牢固的关系。 nafld是 这也是发展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很快将超过乙型肝炎和 酗酒肝硬化是美国肝移植的最常见指征。因此有一个 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。 在这笔赠款中，我们将检查乙酰辅酶A的新型肝脏小分子抑制剂的慢性作用 肝甘油三酸酯含量以及NAFLD受试者中的肝葡萄糖和脂质代谢上的羧化酶 在随机的双盲安慰剂对照平行组研究中。具体而言，我们将检查 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磁共振光谱（MRS）评估的肝甘油三酸酯含量，2）肝骨骼 通过高胰岛素血糖夹夹评估的肌肉和脂肪细胞胰岛素敏感性与 [6,6-2H2]葡萄糖，[2H5]甘油和[13C16]棕榈酸酯周转率，3）肝线粒体氧化速率 通过体内13C磁共振光谱直接评估，4）评估的肝酮发生率 由[13C4]β-羟基丁酸的周转率，5）肝脂肪生成（DNL）和糖异生，由 2H2O，6）由A评估的肝丙酮酸羧化酶通量（VPC）/柠檬酸合酶通量（VC）的相对通量速率 新型的同位素NMR示踪剂分析（PINTA）方法和7）全身能量消耗， VO2，VCO2，通过间接量热法评估的呼吸引号。我们假设慢性抑制 乙酰辅酶A羧化酶会因肝脏线粒体脂肪增加而导致肝脂肪变性降低 氧化和改善的DNL。我们还预计，肝脂肪变性的减少将与 改善了肝胰岛素敏感性，这反映在增加的肝葡萄糖产生期间的抑制作用。 高胰岛素血糖夹。这些研究的结果将提供重要的新概念证明 支持实时靶向的乙酰乙酰辅酶A羧化酶抑制作用的数据作为NAFLD和T2D的疗法以及 对肝靶向乙酰乙酰羧酸酶抑制的机制的基本新见解 减少肝脂肪变性，降低肝胰岛素耐药性并改变肝脏线粒体脂肪氧化。 呢