Dysregulation of lipid homeostasis is common in major human diseases, including type 2 diabetes, obesity, fatty liver diseases, atherosclerosis and some types of cancer. Our laboratory is interested in the transcriptional control of lipid metabolism. In addition to DNA-binding transcription factors, gene expression in eukaryotic cells often requires a series of transcriptional cofactors. We use biochemical and genetic approaches to study the physiological and pathophysiological functions and regulation of the network of transcription factors and their cofactors in the liver (hepatocytes) and adipose tissues (white, brown and beige adipocytes). A focus of our work is the multi-subunit Mediator complex, which is a highly conserved transcriptional cofactor. The mammalian Mediator is one of the cofactors for the sterol regulatory element -binding proteins (SREBP), the master regulators of both fatty acid/triglyceride and cholesterol biosynthesis. SREBP proteins are synthesized as inactive precursors that are tethered to the endoplasmic reticulum membrane. When lipid biosynthesis is demanded, SREBP precursors are proteolytically processed to mature forms of transcription factors that migrate into the nucleus, interact with cofactors including the Mediator complex, and activate transcription of target genes, which encode the rate-limiting enzymes in synthesizing fatty acids/triglycerides and cholesterol. Through the protein-protein interactions of different subunits with SREBP as well as other transcription factors, the Mediator complex critically regulates lipid metabolism. Moreover, dynamic remodeling of the Mediator complex conveys the metabolic signals to transcriptional outputs, providing another layer of regulation of gene expression. With the ultimate goal of identifying novel targets for preventing or treating metabolic syndrome (including type 2 diabetes, obesity, fatty liver disease, hyperlipidemia and hypertension), our research will advance our understanding of how lipid homeostasis is regulated at the molecular level.