CDK8 regulation in alcoholic liver disease

CDK8在酒精性肝病中的调节

• 批准号: 8678167
• 负责人: Fajun James Yang
• 金额: $ 24.01万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678167
• 关键词: ADD-1 protein; Acetylation; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Biochemical; Bioinformatics; CDC2 Protein Kinase; Cell Cycle Regulation; Cell Nucleus; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cirrhosis; Complex; Cultured Cells; Cyclin-Dependent Kinases; Data; Development; Disease; Doctor of Philosophy; Down-Regulation; Endoplasmic Reticulum; Ethanol; Ethanol Metabolism; Fatty Liver; Fibrosis; Genes; Genetic Transcription; Glycogen Synthase Kinase 3; Health; Hepatic; Hepatocyte; Histone Deacetylase; Human; In Vitro; Knock-out; Lead; Lipids; Liver; Lysine; MED15; Mediator of activation protein; Membrane; Modification; Molecular; Molecular Biology; Mus; Mutate; N-terminal; Nature; Nuclear; Organ; Outcome; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Primary carcinoma of the liver cells; Principal Investigator; Proteins; Proteolytic Processing; Public Health; Recruitment Activity; Regulation; Research; Role; Series; Serum; Site; Staging; Steatohepatitis; Surface; Testing; Therapeutic; Transcription Coactivator; Transcription Factor 3; Translating; United States; Yang; adiponectin; base; chronic alcohol ingestion; citrate carrier; cofactor; cyclin C; effective therapy; fatty acid biosynthesis; human CDK2 protein; human disease; in vivo; in vivo Model; innovation; insight; lipid biosynthesis; liver injury; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; problem drinker; protein complex; public health relevance; research study; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a leading cause of liver-related deaths in the United States. Currently there is no effective therapy. This is due to the lack of complete mechanistic understanding on how ethanol metabolism causes organ damage. A common feature of ALD is excessive lipid accumulation in hepatocytes, which is driven by alcohol-induced de novo lipogenesis. As a key transcriptional activator of lipogenic genes, sterol regulatory element-binding protein-1c (SREBP-1c) is activated in ALD. Thus, understanding the regulation of SREBP-1c activation will provide not only novel insights into the molecular mechanisms responsible for the development of ALD, but also therapeutic opportunities for treating ALD. Recently, we found CDK8, a subunit of the Mediator cofactor complex, as a negative regulator of de novo lipogenesis. Mechanistically, CDK8 phosphorylates nuclear form of SREBP-1c, promoting degradation of this transcription factor. Interestingly, our preliminary data show that hepatic CDK8 proteins are decreased in mouse models of ALD and in vitro, suggesting that CDK8 is directly or indirectly targeted by ethanol metabolism. However, it is unknown how ethanol down-regulates CDK8. The central hypothesis of the project is that alcohol abuse causes down- regulation of CDK8, and as a result, nuclear SREBP-1c is accumulated, contributing to ALD. To test the hypothesis, a series of in vivo and in vitro experiments are proposed to determine the role of hepatic CDK8 in the development of ALD and to elucidate the regulatory mechanisms of alcohol- induced down-regulation of CDK8. The long-term objective of the project is to determine the function and regulation of CDK8 in ALD. This application is not only significantly relevant to public health, but also highly innovative an will have positive impacts to the field of alcoholic diseases.

描述（由申请人提供）：酒精性肝病（ALD）是美国肝脏相关死亡的主要原因。目前尚无有效的治疗方法。这是由于对乙醇代谢如何导致器官损伤缺乏完整的机制了解。 ALD 的一个共同特征是肝细胞中脂质过度积累，这是由酒精诱导的从头脂肪生成驱动的。作为脂肪生成基因的关键转录激活因子，甾醇调节元件结合蛋白-1c (SREBP-1c) 在 ALD 中被激活。因此，了解 SREBP-1c 激活的调节不仅将为 ALD 发展的分子机制提供新的见解，而且还为治疗 ALD 提供了治疗机会。最近，我们发现 CDK8（介导辅助因子复合物的一个亚基）作为从头脂肪生成的负调节因子。从机制上讲，CDK8 磷酸化核形式的 SREBP-1c，促进该转录因子的降解。有趣的是，我们的初步数据显示，在 ALD 小鼠模型和体外，肝脏 CDK8 蛋白减少，表明 CDK8 直接或间接受到乙醇代谢的靶向。然而，乙醇如何下调 CDK8 尚不清楚。该项目的中心假设是，酗酒会导致 CDK8 下调，从而导致核 SREBP-1c 积累，从而导致 ALD。为了检验这一假设，我们进行了一系列体内和体外实验，以确定肝脏 CDK8 在 ALD 发展中的作用，并阐明酒精诱导的 CDK8 下调的调节机制。该项目的长期目标是确定CDK8在ALD中的功能和调节。该应用不仅与公共健康密切相关，而且具有高度创新性，将对酒精疾病领域产生积极影响。