The novel adipokine, CTRP3, as an inhibitor of Alcoholic Fatty Liver Disease

新型脂肪因子 CTRP3 作为酒精性脂肪肝的抑制剂

• 批准号: 8969198
• 负责人: Jonathan M Peterson
• 金额: $ 7.3万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969198
• 关键词: Adipocytes; Adipose tissue; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Hepatitis; Alcohols; Antioxidants; Apoptotic; Attenuated; Cause of Death; Cessation of life; Chronic; Chronic Hepatitis; Cirrhosis; Complement 1q; Data; Development; Diet; Disease Progression; Ethanol; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Funding; Gene Expression; Goals; Health; Heavy Drinking; Hepatic; Hepatitis; Hepatocyte; In Vitro; Inflammatory; Knowledge; Lipids; Liver; Liver diseases; Measures; Mediating; Modeling; Mus; Oxidative Stress; Pathogenesis; Patients; Pharmacologic Substance; Pharmacological Treatment; Production; Proteins; Public Health; Publications; Regulation; Research; Research Design; Risk; Role; SRE-1 binding protein; Signal Pathway; TNF gene; Testing; Therapeutic; Transgenic Organisms; United States; United States National Institutes of Health; Wild Type Mouse; Work; alcohol effect; alcohol exposure; base; chronic alcohol ingestion; cytokine; design; feeding; in vivo; inhibitor/antagonist; innovation; insight; lipid biosynthesis; lipid metabolism; liver inflammation; mortality; non-alcoholic fatty liver; novel; novel therapeutic intervention; overexpression; oxidation; prevent; problem drinker; public health relevance; therapeutic target

 DESCRIPTION (provided by applicant): Our goal is to identify the potential role of the novel adipose tissue-derived factor, C1q TNF Related Protein 3 (CTRP3), as a therapeutic target to treat/prevent alcoholic fatty liver disease (AFLD). Background: Alcoholic fatty liver disease (AFLD) is a significant public health concern. Cirrhosis is the 12th leading cause of death in the United States with approximately half of its cases attributed to AFLD. Currently, there are no known pharmacological treatments available to treat AFLD. Rationale: We identified a novel adipose tissue-derived factor, CTRP3, which significantly inhibits high fat diet-induced hepatic steatosis. The CTRP3 levels, however, may be reduced with alcohol consumption. The inhibitory effect of CTRP3 on alcoholic-induced hepatic steatosis and reduction in CTRP3 levels in ALFD has not been established. Hypothesis: CTRP3 attenuates alcoholic-induced hepatic lipid accumulation. Specific Aims: 1) to determine whether increased circulating CTRP3 levels can reduce alcohol-induced hepatic lipid accumulation and 2) to confirm that alcohol exposure reduces circulating CTRP3 levels. These aims are designed to establish not only the beneficial effect of CTRP3 towards preventing AFLD, but also show that normal CTRP3 levels are suppressed by alcohol consumption. These data will identify the potential pharmaceutical impact of CTRP3 treatment. Research Design: To test our hypothesis we will determine the ability of transgenic overexpression of CTRP3 (CTRP3 Tg) to prevent alcohol-induced hepatic lipid accumulation in mice. Further, we will examine the effects of alcohol-feeding on circulating CTRP3 levels in wild type mice. Relevance: The proposed research is highly innovative since it examines a completely novel mechanism that leads to AFLD. Additionally, the proposed research has the potential for high impact since CTRP3 may be used clinically as a treatment for AFLD.

 描述(申请人提供)：我们的目标是确定新型脂肪组织衍生因子C1q肿瘤坏死因子相关蛋白3(CTRP3)作为治疗靶点治疗/预防酒精性脂肪性肝病(AFLD)的潜在作用。背景：酒精性脂肪性肝病(AFLD)是一个重大的公共卫生问题。在美国，肝硬变是第12大死因，大约一半的病例是由AFLD引起的。目前，还没有已知的治疗AFLD的药物治疗方法。理论基础：我们发现了一种新的脂肪组织衍生因子CTRP3，它能显著抑制高脂饮食诱导的肝脏脂肪变性。然而，CTRP3水平可能会随着饮酒而降低。CTRP3对酒精性肝脂肪变性和ALFD中CTRP3水平降低的抑制作用尚未确定。假设：CTRP3可减轻酒精诱导的肝脏脂肪堆积。具体目的：1)确定增加循环CTRP3水平是否可以减少酒精诱导的肝脏脂质堆积；2)证实酒精暴露降低循环CTRP3水平。这些目的不仅是为了确定CTRP3对预防AFLD的有益作用，也是为了表明正常的CTRP3水平受到酒精消费的抑制。这些数据将确定CTRP3治疗的潜在药学影响。研究设计：为了验证我们的假设，我们将确定转基因过表达CTRP3(CTRP3TG)对防止酒精诱导的小鼠肝脏脂质堆积的能力。此外，我们将研究酒精喂养对野生型小鼠循环CTRP3水平的影响。相关性：这项拟议的研究具有很高的创新性，因为它研究了一种导致AFLD的全新机制。此外，由于CTRP3可能被用于临床治疗AFLD，因此拟议的研究具有很大的影响。