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

doi:10.1016/j.celrep.2014.06.006

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

Biology

Research output: Contribution to journal › Article › peer-review

33 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 language	English
Pages (from-to)	242-255
Number of pages	14
Journal	Cell Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2014.06.006
State	Published - 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

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2014.06.006

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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.",

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

note = "Funding Information: We thank members of J.R.{\textquoteright}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. ",

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AU - Wu, Xiaoying

AU - Romero, Donna

AU - Swiatek, Wojciech I.

AU - Dorweiler, Irene

AU - Kikani, Chintan K.

AU - Sabic, Hana

AU - Zweifel, Ben S.

AU - McKearn, John

AU - Blitzer, Jeremy T.

AU - Nickols, G. Allen

AU - Rutter, Jared

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PY - 2014/7/10

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N2 - 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.

AB - 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.

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JF - Cell Reports

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ER -

PAS kinase drives lipogenesis through SREBP-1 maturation

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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