PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity

J Clin Invest. 2003 Sep;112(6):935-44. doi: 10.1172/JCI18816.


PKClambda is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKClambda specifically in the liver (L-lambdaKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element-binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-lambdaKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKClambda and was mimicked by overexpression of WT PKClambda. Restoration of PKClambda expression in the liver of L-lambdaKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism*
  • Isoenzymes
  • Lipid Metabolism*
  • Liver / chemistry
  • Liver / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Rats
  • Sterol Regulatory Element Binding Protein 1
  • Tissue Distribution
  • Transcription Factors / metabolism


  • Blood Glucose
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Insulin
  • Isoenzymes
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • protein kinase C eta
  • Protein Kinase C
  • protein kinase C lambda