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.
Principal Investigator: Fajun Yang, Ph.D. Project Narrative (Public Health Relevance Statement) Alcoholic liver disease is a prevalent health problem in the United States. Alcohol abuse causes fatty liver largely due to the elevation of hepatic lipid biosynthesis. Excessive lipid accumulation in the liver will lead to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The proposed research will study the novel mechanism and function of CDK8 in controlling ethanol-induced lipid biosynthesis. Thus, the outcomes of this project will guide the development of novel therapeutic approaches, and will have a significant impact on the treatment of human alcoholic liver disease.