PAS Kinase Regulates Hepatic Lipid Metabolism through Activating SREBP‐1

Abstract

PAS kinase (PASK) is a serine/threonine protein kinase conserved from yeast to human. PASK activity has been shown to be controlled by nutrient status, but its roles in regulating metabolism remain largely unclear. In order to study the function of PASK in mammals, we used PASK deficient (PASK−/−) mice as a model system. PASK−/− mice showed decreased liver accumulation of triglyceride induced by a high‐fat diet. This was accompanied by lower expression levels of glycerol‐3‐phosphate acyltransferase 1 (GPAT1), stearoyl‐CoA desaturase 1 (SCD1) and fatty acid elongase (FAE), three important enzymes responsible for biosynthesis of fatty acids and triglyceride. We also observed the down‐regulation of these genes upon PASK knockdown in cultured HepG2 (Hepatocellular carcinoma, human) cells. The expression of GPAT1, SCD1 and FAE are regulated by a family of transcription factors called sterol regulatory element binding proteins (SREBPs). Our data suggests that PASK promotes the activity of SREBP‐1, probably by enhancing the processing of the SREBP‐1 precursor to form the active nuclear form. We are now trying to determine the detailed mechanisms of how PASK regulates the processing step. These studies will further our understanding of the physiological roles of PASK, and hopefully provide a potential therapeutic target for metabolic diseases.