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Regulation of lipogenesis by cyclin-dependent kinase 8–mediated control of SREBP-1
Xiaoping Zhao, … , Jun-Yuan Ji, Fajun Yang
Xiaoping Zhao, … , Jun-Yuan Ji, Fajun Yang
Published June 11, 2012
Citation Information: J Clin Invest. 2012;122(7):2417-2427. https://doi.org/10.1172/JCI61462.
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Research Article Metabolism Article has an altmetric score of 7

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

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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.

Authors

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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Figure 4

CDK8 and CycC regulate SREBP-1 protein stability.

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CDK8 and CycC regulate SREBP-1 protein stability.
(A) Effects of CDK8 an...
(A) Effects of CDK8 and CycC knockdown on protein levels of FAS and SREBP-1 in HepG2 cells. (B) Effects of CDK8 knockdown on protein levels of overexpressed Flag-tagged nuclear SREBP-1a in HEK293 cells. The HA-tagged fusion protein of the transactivation domain of Myb and Gal4 DNA-binding domain served as control. (C) Representative immunoblots and (D) relative levels of overexpressed Flag-tagged nuclear SREBP-1a in HEK293 cells in the presence of cycloheximide (CHX) for the indicated amount of time after CDK8 or CycC knockdown. (E) Effects of CDK8 or CycC knockdown on SREBP-1a ubiquitination. Flag-tagged nuclear SREBP-1a was cotransfected with HA-tagged ubiquitin (HA-Ub) and the indicated shRNA plasmids in HEK293 cells. After approximately 40 hours of culture followed by 3 hours of treatment with 0.1 mM MG132, cell lysates were prepared. The amount of SREBP-1a proteins was normalized after immunoprecipitation from cell lysate, and the presence of HA-ubiquitin modifications was detected by immunoblotting using anti-HA antibody. (F) Endogenous nuclear SREBP-1 proteins were immunoprecipitated from HEK293 cells after lentiviral CDK8 (or NS) shRNA treatment for 48 hours, followed by 3 hours of treatment with 0.1 mM MG132. The presence of ubiquitinated proteins was detected by anti-ubiquitin antibody.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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