Regulation of lipogenesis by cyclin-dependent kinase 8 - Mediated control of SREBP-1

Xiaoping Zhao, Daorong Feng, Qun Wang, Arian Abdulla, Xiao Jun Xie, Jie Zhou, Yan Sun, Ellen S. Yang, Lu Ping Liu, Bhavapriya Vaitheesvaran, Lauren Bridges, Irwin J. Kurland, Randy Strich, Jian Quan Ni, Chenguang Wang, Johan Ericsson, Jeffrey E. Pessin, Jun Yuan Ji, Fajun Yang

Research output: Contribution to journalArticle

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Abstract

Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein degradation. Importantly, consistent with the physiologic regulation of lipid biosynthesis, CDK8 and CycC proteins were rapidly downregulated by feeding and insulin, resulting in decreased SREBP-1c phosphorylation. Moreover, overexpression of CycC efficiently suppressed insulin and feeding-induced lipogenic gene expression. Taken together, these results demonstrate that CDK8 and CycC function as evolutionarily conserved components of the insulin signaling pathway in regulating lipid homeostasis.

Original languageEnglish (US)
Pages (from-to)2417-2427
Number of pages11
JournalJournal of Clinical Investigation
Volume122
Issue number7
DOIs
StatePublished - Jul 2 2012

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Cyclin-Dependent Kinase 8
Cyclin C
Lipogenesis
Sterol Regulatory Element Binding Protein 1
Insulin
Phosphorylation
Lipid Metabolism
Sterol Regulatory Element Binding Proteins
Lipids
Ubiquitination
Liver
Threonine
Type 2 Diabetes Mellitus
Proteolysis
Drosophila
Hepatocytes
Homeostasis
Transcription Factors
Down-Regulation
Obesity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Regulation of lipogenesis by cyclin-dependent kinase 8 - Mediated control of SREBP-1. / Zhao, Xiaoping; Feng, Daorong; Wang, Qun; Abdulla, Arian; Xie, Xiao Jun; Zhou, Jie; Sun, Yan; Yang, Ellen S.; Liu, Lu Ping; Vaitheesvaran, Bhavapriya; Bridges, Lauren; Kurland, Irwin J.; Strich, Randy; Ni, Jian Quan; Wang, Chenguang; Ericsson, Johan; Pessin, Jeffrey E.; Ji, Jun Yuan; Yang, Fajun.

In: Journal of Clinical Investigation, Vol. 122, No. 7, 02.07.2012, p. 2417-2427.

Research output: Contribution to journalArticle

Zhao, X, Feng, D, Wang, Q, Abdulla, A, Xie, XJ, Zhou, J, Sun, Y, Yang, ES, Liu, LP, Vaitheesvaran, B, Bridges, L, Kurland, IJ, Strich, R, Ni, JQ, Wang, C, Ericsson, J, Pessin, JE, Ji, JY & Yang, F 2012, 'Regulation of lipogenesis by cyclin-dependent kinase 8 - Mediated control of SREBP-1', Journal of Clinical Investigation, vol. 122, no. 7, pp. 2417-2427. https://doi.org/10.1172/JCI61462
Zhao, Xiaoping ; Feng, Daorong ; Wang, Qun ; Abdulla, Arian ; Xie, Xiao Jun ; Zhou, Jie ; Sun, Yan ; Yang, Ellen S. ; Liu, Lu Ping ; Vaitheesvaran, Bhavapriya ; Bridges, Lauren ; Kurland, Irwin J. ; Strich, Randy ; Ni, Jian Quan ; Wang, Chenguang ; Ericsson, Johan ; Pessin, Jeffrey E. ; Ji, Jun Yuan ; Yang, Fajun. / Regulation of lipogenesis by cyclin-dependent kinase 8 - Mediated control of SREBP-1. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 7. pp. 2417-2427.
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AU - Xie, Xiao Jun

AU - Zhou, Jie

AU - Sun, Yan

AU - Yang, Ellen S.

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AU - Kurland, Irwin J.

AU - Strich, Randy

AU - Ni, Jian Quan

AU - Wang, Chenguang

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AU - Ji, Jun Yuan

AU - Yang, Fajun

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