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: 9145611
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145611
• 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; Disease Progression; Ethanol; Fatty Liver; Fibrosis; Funding; Gene Expression; Goals; Health; Heavy Drinking; Hepatic; Hepatitis; Hepatocyte; High Fat Diet; In Vitro; Inflammatory; Knowledge; Lipids; Liver; Liver diseases; Measures; Mediating; Modeling; Mus; Oxidative Stress; PPAR alpha; 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（由适用提供）：我们的目标是确定新型脂肪组织衍生因子C1Q TNF相关蛋白3（CTRP3）的潜在作用，作为治疗/预防酒精性脂肪肝病（AFLD）的治疗靶标。背景：酒精脂肪肝病（AFLD）是一个重大的公共健康问题。肝硬化是美国的第十二个主要死因，其病例中约有一半归因于AFLD。目前，尚无已知的药理治疗方法来治疗AFLD。理由：我们确定了一种新型的脂肪组织衍生的因子Ctrp3，该因子显着抑制了高脂肪饮食诱导的肝脂肪变性。但是，随着饮酒量，CTRP3水平可能会降低。 CTRP3对ALFD中酒精诱导的肝脂肪变性和CTRP3水平降低的抑制作用没有假设：Ctrp3减弱了酒精诱导的肝脂质的积累。具体目的：1）确定循环升高的CTRP3水平是否可以降低酒精诱导的肝脂质积累，2）确认酒精暴露会降低循环CTRP3水平。这些目标不仅旨在建立CTRP3对防止AFLD的有益效果，而且还表明饮酒量抑制了正常的CTRP3水平。这些数据将确定CTRP3处理的潜在药物影响。研究设计：为了检验我们的假设，我们将确定CTRP3（CTRP3 TG）的转基因过表达的能力，以防止小鼠酒精诱导的肝脂质积累。此外，我们将检查饮酒对野生型小鼠循环CTRP3水平的影响。相关性：拟议的研究具有很高的创新性，因为它研究了导致AFLD的完全新颖的机制。此外，拟议的研究具有高影响力的潜力，因为CTRP3可以在临床上用作AFLD的治疗方法。

项目成果

Identification of Putative Receptors for the Novel Adipokine CTRP3 Using Ligand-Receptor Capture Technology.

• DOI: 10.1371/journal.pone.0164593
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Li Y;Ozment T;Wright GL;Peterson JM
• 通讯作者: Peterson JM

The sex specific effect of alcohol consumption on circulating levels of CTRP3.

• DOI: 10.1371/journal.pone.0207011
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: DeGroat AR;Fleming CK;Dunlay SM;Hagood KL;Moorman JP;Peterson JM
• 通讯作者: Peterson JM

Divergent relationship of circulating CTRP3 levels between obesity and gender: a cross-sectional study.

• DOI: 10.7717/peerj.2573
• 发表时间: 2016
• 期刊: PeerJ
• 影响因子: 2.7
• 作者: Wagner RM;Sivagnanam K;Clark WA;Peterson JM
• 通讯作者: Peterson JM

Transgenic overexpression of CTRP3 prevents alcohol-induced hepatic triglyceride accumulation.

CTRP3 的转基因过度表达可防止酒精诱导的肝脏甘油三酯积累。

• DOI: 10.1152/ajpendo.00050.2018
• 发表时间: 2018
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Trogen,Greta;Bacon,Joshua;Li,Ying;Wright,GaryL;Degroat,Ashley;Hagood,KendraL;Warren,Zachary;Forsman,Allan;Kilaru,Aruna;Clark,WAndrew;Peterson,JonathanM
• 通讯作者: Peterson,JonathanM

The adipokine C1q TNF related protein 3 (CTRP3) is elevated in the breast milk of obese mothers.

• DOI: 10.7717/peerj.4472
• 发表时间: 2018
• 期刊: PeerJ
• 影响因子: 2.7
• 作者: Kwon MR;Cress E;Clark WA;Alamian A;Lu Y;Peterson JM
• 通讯作者: Peterson JM