CDK8 regulation in alcoholic liver disease

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引起器官损伤缺乏完整的机制理解。ALD的一个共同特征是肝细胞中过量的脂质积累，这是由酒精诱导的从头脂肪生成驱动的。甾醇调节元件结合蛋白-1c （SREBP-1c）是脂肪生成基因的关键转录激活因子，在ALD中被激活。因此，了解SREBP-1c活化的调控不仅将为ALD发展的分子机制提供新的见解，而且还将为治疗ALD提供治疗机会。最近，我们发现CDK8，调解辅助因子复合物的一个亚基，作为新的脂肪生成的负调节因子。从机制上讲，CDK8磷酸化SREBP-1c的核形式，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，这表明CDK8是乙醇代谢的直接或间接靶点。然而，乙醇是如何下调CDK8的尚不清楚。该项目的中心假设是，酒精滥用导致CDK8下调，因此，核SREBP-1c积累，导致ALD。为了验证这一假设，我们提出了一系列体内和体外实验来确定肝脏CDK8在ALD发展中的作用，并阐明酒精诱导CDK8下调的调控机制。该项目的长期目标是确定CDK8在ALD中的功能和调控。这一应用不仅与公共卫生密切相关，而且具有高度创新性，将对酒精疾病领域产生积极影响。

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.