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

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.

DOI: 10.1172/JCI61462

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@article{Zhao2012RegulationOL, title={Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1.}, author={Xiaoping Zhao and Daorong Feng and Qun Wang and Arian Abdulla and Xiao-Jun Xie and Jie Zhou and Yan Sun and Ellen S.T. Yang and Lu-ping Liu and Bhavapriya Vaitheesvaran and Lauren Bridges and Irwin Jack Kurland and Randy Strich and Jian-quan Ni and Chenguang Wang and Johan Ericsson and Jeffrey E . Pessin and Jun-Yuan Ji and FaJun Yang}, journal={The Journal of clinical investigation}, year={2012}, volume={122 7}, pages={2417-27} }