ACC enzymes and protein acetylation

ACC 酶和蛋白质乙酰化

• 批准号: 8934082
• 负责人: Kyle Lee hoehn
• 金额: $ 35.55万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-27 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934082
• 关键词: Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Acetylation; Acetyltransferase; Acute; Address; Affect; Alleles; American; Area; Birth; Cardiovascular Diseases; Chronic; Clinic; Clinical; Data; Deacetylase; Deposition; Development; Diet; Disease; Drug Targeting; Enzymes; Exhibits; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Future; Gene Expression; Glucose; Glucose Intolerance; Health; Hepatic; In Vitro; Insulin Resistance; Knockout Mice; Lead; Left; Life; Lipids; Liver; Liver diseases; Malonyl Coenzyme A; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methionine; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiology; Primary carcinoma of the liver cells; Production; Protein Acetylation; Proteins; Reaction; Regulation; Residual state; Resistance; Role; Steatohepatitis; Testing; Tissues; Triglycerides; Work; aged; aminoglycoside N1-acetyltransferase; base; blood glucose regulation; choline deficient diet; diabetic patient; effective therapy; feeding; glucose metabolism; glucose output; glucose tolerance; improved; in vivo; inhibitor/antagonist; lipid metabolism; liver metabolism; mutant; novel; prevent; small molecule

DESCRIPTION (provided by applicant): Fatty liver disorders affect more than 20% of Americans; however, there are no effective treatment options. The enzymes acetyl-CoA carboxylase (ACC) 1 and ACC2 promote fat synthesis in the liver; therefore, they are attractive drug targets for fatty liver disease and related disorders. To determine how the loss of ACC activity in the liver affects hepatic and whole body metabolism, we generated liver-specific ACC1 and ACC2 double knockout mice (LDKO). We find that these mice are protected from diet-induced glucose intolerance, but accumulate an unexpected increase in liver fat. Our preliminary data suggest that when ACC enzymes are inhibited their substrate acetyl-CoA is used for protein acetylation. In this study we will test the consequences of long-term ACC inhibition on fatty liver disease pathologies and we will determine whether maintaining some residual ACC activity at ACC1 or ACC2 may uncouple the positive effects on glucose tolerance from the increased fat accumulation by preventing protein hyper-acetylation. This work will advance our understanding of the molecular regulation of liver metabolism by ACC enzymes. In addition, this study will guide future pharmacology in the area of developing liver-targeted isotype-sparing ACC inhibitors for the treatment fatty liver disease and related metabolic disorders.

描述（由申请人提供）：脂肪肝疾病影响超过20%的美国人;然而，没有有效的治疗方案。乙酰辅酶A羧化酶（ACC）1和ACC 2促进肝脏中的脂肪合成;因此，它们是脂肪肝疾病和相关疾病的有吸引力的药物靶点。为了确定肝脏中ACC活性的丧失如何影响肝脏和全身代谢，我们产生了肝脏特异性ACC 1和ACC 2双敲除小鼠（LDKO）。我们发现，这些小鼠免受饮食诱导的葡萄糖耐受不良的影响，但肝脏脂肪却意外增加。我们的初步数据表明，当ACC酶被抑制时，它们的底物乙酰辅酶A用于蛋白质乙酰化。在这项研究中，我们将测试长期ACC抑制对脂肪肝疾病病理学的影响，并确定在ACC 1或ACC 2处保持一些残留的ACC活性是否可以通过防止蛋白质过度乙酰化来解除对葡萄糖耐量的积极影响。这项工作将促进我们对ACC酶对肝脏代谢的分子调控的理解。此外，这项研究将指导未来的药理学领域开发肝脏靶向的同种型保留ACC抑制剂，用于治疗脂肪肝疾病和相关代谢紊乱。