Glucose represses PPARα gene expression via AMP-activated protein kinase but not via p38 mitogen-activated protein kinase in the pancreatic β-cell

J Diabetes. 2009 Dec;1(4):263-72. doi: 10.1111/j.1753-0407.2009.00043.x. Epub 2009 Jul 8.


Background: Peroxisome proliferator-activated receptor α (PPARα) regulates the expression of fatty acid metabolism genes and is thought to play a role in the regulation of insulin secretion and lipid detoxification. We have examined the mechanism whereby glucose decreases PPARα gene expression in the pancreatic β-cell.

Methods: INS832/13 β-cell and isolated rat islets were incubated at 3 and 20 mM glucose for 18 h in the absence or presence of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators and inhibitors, as well as p38 mitogen-activated protein kinase (p38 MAPK) inhibitors. In another set of experiments, INS832/13 were infected with an adenovirus expressing a dominant-negative form of AMPK. PPARα expression levels were measured by reverse transcription polymerase chain reaction and Western blot.

Results: Elevated glucose reduced the abundance of the PPARα transcript and protein, and its target genes acyl-coenzyme A (CoA) oxidase (ACO) and uncoupling protein 2 (UCP-2) in INS832/13 β-cell and isolated rat islets. Glucose reduced AMPK activity, while the AMPK activators 5-amino-4-imidazolecarboxamide riboside and metformin increased PPARα expression and suppressed the action of glucose. By contrast, the AMPK inhibitor compound C mimicked the glucose effect. A dominant negative form of AMPKα reduced the PPARα, ACO and UCP-2 transcripts to the same extent as elevated glucose. Pharmacological evidence indicated that glucose-regulated PPARα expression does not involve p38 MAPK, a target of AMPK in several cell types.

Conclusions: The results indicate that glucose represses PPARα gene expression via AMPK, but not via p38 MAPK in the β-cell.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • DNA Primers
  • Down-Regulation
  • Gene Expression / drug effects*
  • Glucose / pharmacology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / physiology*
  • PPAR alpha / drug effects
  • PPAR alpha / genetics*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • DNA Primers
  • PPAR alpha
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • Glucose