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

 描述（由申请人提供）：我们的目标是确定新型脂肪组织衍生因子C1 q TNF相关蛋白3（CTRP 3）作为治疗/预防酒精性脂肪肝（AFLD）的治疗靶点的潜在作用。背景：酒精性脂肪性肝病（AFLD）是一个重要的公共卫生问题。肝硬化是美国第12大死亡原因，其中约一半的病例归因于AFLD。目前，没有已知的药物治疗可用于治疗AFLD。基本原理：我们发现了一种新的脂肪组织衍生因子CTRP 3，它能显著抑制高脂饮食诱导的肝脂肪变性。然而，CTRP 3水平可能会随着饮酒而降低。CTRP 3对酒精诱导的肝脂肪变性的抑制作用和ALFD中CTRP 3水平的降低尚未确定。假设：CTRP 3减弱酒精诱导的肝脏脂质蓄积。具体目标：1）确定增加的循环CTRP 3水平是否可以减少酒精诱导的肝脏脂质积累，以及2）确认酒精暴露降低循环CTRP 3水平。这些目标不仅旨在确定CTRP 3对预防AFLD的有益作用，而且还表明正常CTRP 3水平受到酒精消费的抑制。这些数据将确定CTRP 3治疗的潜在药物影响。研究设计：为了检验我们的假设，我们将确定转基因过表达CTRP 3（CTRP 3 Tg），以防止酒精诱导的小鼠肝脏脂质积累的能力。此外，我们将研究酒精喂养对野生型小鼠循环CTRP 3水平的影响。相关性：拟议的研究具有高度创新性，因为它研究了导致AFLD的全新机制。此外，由于CTRP 3可在临床上用作AFLD的治疗，因此拟议的研究具有高影响力的潜力。

 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.