title: PAS kinase drives lipogenesis through SREBP-1 maturation.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112-5650, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wu
authors.affiliation: Synergenics, 1700 Owens Street, Suite 515, San Francisco, CA 94158, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Romero
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112-5650, USA.
authors.forename: Wojciech I
authors.initials: WI
authors.lastname: Swiatek
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112-5650, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Dorweiler
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112-5650, USA.
authors.forename: Chintan K
authors.initials: CK
authors.lastname: Kikani
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112-5650, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Sabic
authors.affiliation: Synergenics, 1700 Owens Street, Suite 515, San Francisco, CA 94158, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Zweifel
authors.affiliation: Synergenics, 1700 Owens Street, Suite 515, San Francisco, CA 94158, USA.
authors.forename: John
authors.initials: J
authors.lastname: McKearn
authors.affiliation: Synergenics, 1700 Owens Street, Suite 515, San Francisco, CA 94158, USA.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Blitzer
authors.affiliation: Synergenics, 1700 Owens Street, Suite 515, San Francisco, CA 94158, USA.
authors.forename: G Allen
authors.initials: GA
authors.lastname: Nickols
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112-5650, USA. Electronic address: rutter@biochem.utah.edu.
authors.forename: Jared
authors.initials: J
authors.lastname: Rutter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050171:Dyslipidemias / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D051780:Sterol Regulatory Element Binding Protein 1; C116037:PAS domain kinases; D017346:Protein Serine-Threonine Kinases