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

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

Author information

1
Montreal Diabetes Research Center and CRCHUM, Montréal, Québec, Canada. erik.joly@crchum.qc.ca

Abstract

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.

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