Summary 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 the 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 pharmacologic approaches, that PASK is required for the proteolytic maturation of SREBP-1c in cultured cells and in 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.