Regulation of Lipogenesis by Cyclin-Dependent Kinase 8-mediated Control of SREBP-1

J Clin Invest. 2012 Jul;122(7):2417-27. doi: 10.1172/JCI61462. Epub 2012 Jun 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Cyclin C / genetics
  • Cyclin C / metabolism
  • Cyclin-Dependent Kinase 8 / genetics
  • Cyclin-Dependent Kinase 8 / metabolism
  • Cyclin-Dependent Kinase 8 / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Fasting / metabolism
  • Fat Body / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Hepatocytes / metabolism
  • Humans
  • Larva / metabolism
  • Lipogenesis*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Primary Cell Culture
  • Protein Processing, Post-Translational
  • Protein Stability
  • RNA Interference
  • Rats
  • Sterol Regulatory Element Binding Protein 1 / metabolism*

Substances

  • CycC protein, Drosophila
  • Cyclin C
  • Drosophila Proteins
  • Sterol Regulatory Element Binding Protein 1
  • Cdk8 protein, Drosophila
  • Cyclin-Dependent Kinase 8