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

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109 Scopus citations

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

ASJC Scopus subject areas

  • Medicine(all)

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    Zhao, X., Feng, D., Wang, Q., Abdulla, A., Xie, X. J., Zhou, J., Sun, Y., Yang, E. S., Liu, L. P., Vaitheesvaran, B., Bridges, L., Kurland, I. J., Strich, R., Ni, J. Q., Wang, C., Ericsson, J., Pessin, J. E., Ji, J. Y., & Yang, F. (2012). Regulation of lipogenesis by cyclin-dependent kinase 8 - Mediated control of SREBP-1. Journal of Clinical Investigation, 122(7), 2417-2427. https://doi.org/10.1172/JCI61462