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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 3

CDK8 and CycC regulate SREBP-1–dependent lipogenic gene expression in mammalian hepatocytes.

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CDK8 and CycC regulate SREBP-1–dependent lipogenic gene expression in ma...
(A and D) Immunoblots for the indicated proteins in primary rat hepatocytes after treatment with lentivirus expressing the indicated shRNA. Pre-SREBP-1, precursor SREBP-1; nSREBP-1, nuclear SREBP-1. (B) Effects of CDK8 or CycC knockdown by lentiviral shRNA on triglyceride levels in isolated primary rat hepatocytes. (C) Effect of CDK8 or CycC knockdown by shRNA on FAS promoter–driven firefly luciferase mRNA levels in HepG2 cells as measured by qRT-PCR. The β-actin–driven Renilla luciferase served as control. (E) mRNA levels of endogenous SREBP target genes in primary rat hepatocytes were detected by qRT-PCR after treatments of the indicated lentiviral shRNA. Cyclophilin B served as the invariant control, and the mRNA levels of each gene were normalized to those in the non-silencing (NS) shRNA–treated sample. Data represent mean ± SD of 3 independent treatments. *P < 0.01 versus control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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