CDK8 regulation in alcoholic liver disease

描述(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。目前还没有有效的治疗方法。这是由于对酒精代谢如何导致器官损伤缺乏完整的机制了解。酒精性肝病的一个共同特征是肝细胞内脂肪过度堆积，这是由酒精诱导的从头脂肪生成所驱动的。固醇调节元件结合蛋白-1c(SREBP-1c)作为成脂基因的关键转录激活因子，在ALD中被激活。因此，了解SREBP-1c激活的调控机制不仅将为ALD的发生发展提供新的分子机制，而且将为ALD的治疗提供新的机会。最近，我们发现CDK8是介体辅助因子复合体的一个亚单位，是新生脂肪生成的负调控因子。在机制上，CDK8使SREBP-1c的核型磷酸化，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小鼠模型和体外实验中，肝脏CDK8蛋白表达减少，这表明CDK8直接或间接地受到乙醇代谢的靶向。然而，乙醇如何下调CDK8的表达尚不清楚。该项目的中心假设是酒精滥用导致CDK8下调，结果是核SREBP-1c积累，导致ALD。为了验证这一假说，我们进行了一系列体内和体外实验，以确定肝脏CDK8在ALD发生发展中的作用，并阐明酒精诱导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。这一应用不仅对公众健康具有重大意义，而且具有很高的创新性，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.