PAS kinase drives lipogenesis through SREBP-1 maturation

Xiaoying Wu, Donna Romero, Wojciech I. Swiatek, Irene Dorweiler, Chintan K. Kikani, Hana Sabic, Ben S. Zweifel, John McKearn, Jeremy T. Blitzer, G. Allen Nickols, Jared Rutter

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)242-255
Number of pages14
JournalCell Reports
Volume8
Issue number1
DOIs
StatePublished - Jul 10 2014

Bibliographical note

Funding Information:
We thank members of J.R.’s lab for helpful discussions; Ryan Doering and Addie Walkup for assistance with the mouse studies; John M. McCall for support with the medicinal chemistry; Phil Needleman, William J. Rutter, and Brendan Manning for helpful advice; Tim Osborne for the pSRE-Luc, pSREBP-1c-Luc and 2xFlag-mSREBP-1a constructs; Wesley I. Sundquist for the pQCXIN-GFP construct; and Alan Diehl for a tagged-SREBP-1 plasmid. This work was supported by the NIH (RO1DK071962 to J.R.) and Synergenics. D.R., W.I.S., I.D., H.S., B.S.Z., J.M., J.T.B., G.A.N., and J.R. are employees, consultants, and/or shareholders of BioEnergenix, LLC.

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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