The Role of the Mediator Complex in the Transcriptional Regulation of Lipogenesis

University Of California Berkeley, Berkeley CA

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Abstract

? DESCRIPTION (provided by applicant): Fatty acid synthase (FAS) is a principal enzyme in the regulation of lipogenesis. The synthesis of fatty acids is an energy expensive process and so the transcription of FAS is tightly regulated by an organism's nutritional state. FAS transcription is low during fasting and increases drastically in the fed state. The concentration o insulin in circulation parallels that of metabolic fuels and is largely responsible for the increas in FAS transcription upon feeding. USF-1 is a critical component of lipogenic gene transcription and its binding to the FAS promoter region is required for FAS transcription. In the presence of elevated insulin, USF is phosphorylated by DNA-PK and subsequently acetylated by P/CAF. Elevated insulin also leads to the phosphorylation of BAF60c, by aPKC, which allows it to interact with phosphorylated/acetylated USF and connect it to other BAF subunits, resulting in the formation of the LipoBAF complex to promote the transcription of FAS and other lipogenic genes. The goals of the proposed work are to examine the interactions identified between USF and Mediator Complex subunits MED17 and CDK8 which finally link USF to the general transcriptional machinery. We propose the following specific aims: Aim 1) to characterize the interaction between USF and MED17 and examine its role in FAS promoter activation, Aim 2) to assess the role of CDK8 in the USF- Mediator Complex interaction and determine whether it is required for FAS promoter activation, and Aim 3) to examine the in vivo metabolic effects of these proteins in liver by adenovirus mediated knockdown and overexpression. We will determine the metabolic significance of these proteins by examining hepatic lipogenesis, as well as levels of triglycerides and other lipids in circulation which can potentially affect insulin sensitivity. This work will allow us to further the understanding of the mechanisms behind insulin-dependent transcriptional activation of lipogenic genes, and may allow us to identify new therapeutic target(s) for metabolic diseases associated with dysregulation of lipid metabolism, such as obesity, hepatosteatosis, and type 2 diabetes.