PAS Kinase Drives Lipogenesis through SREBP-1 Maturation

Elevated hepatic synthesis of fatty acids and triglycerides, driven by hyperactivation of the SREBP-1c transcription factor, has been implicated as a causal feature of metabolic syndrome. SREBP-1c activation requires the proteolytic maturation of the endoplasmic-reticulum-bound precursor to the active, nuclear transcription factor, which is stimulated by feeding and insulin signaling. Here, we show that feeding and insulin stimulate the hepatic expression of PASK. We also demonstrate, using genetic and pharmacological approaches, that PASK is required for the proteolytic maturation of SREBP-1c in cultured cells and in the mouse and rat liver. Inhibition of PASK improves lipid and glucose metabolism in dietary animal models of obesity and dyslipidemia. Administration of a PASK inhibitor decreases hepatic expression of lipogenic SREBP-1c target genes, decreases serum triglycerides, and partially reverses insulin resistance. While the signaling network that controls SREBP-1c activation is complex, we propose that PASK is an important component with therapeutic potential. [Display omitted] •PASK is required for feeding- and insulin-induced expression of lipogenic genes•PASK activates SREBP-1 by promoting its maturation•PASK inhibitor improves hepatic and whole-body dyslipidemia in obese rats Hepatic steatosis is a prominent feature of many metabolic diseases. Elevated lipogenesis is driven mainly by the sterol regulatory element binding protein (SREBP)-1 transcription factor. Here, Wu et al. show that PAS kinase (PASK) promotes SREBP-1 proteolytic maturation, a step required for its activation, in cultured cells and the rodent liver. Genetic or pharmacological inhibition of PASK decreases hepatic expression of SREBP-1 target genes and lipogenesis. This makes PASK a potential therapeutic target for metabolic diseases.