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Coactivator PGC-1alpha regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary

Satu Arpiainen1, Sanna-Mari Järvenpää, Aki Manninen

  • 1Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.

Toxicology and Applied Pharmacology
|July 8, 2008
PubMed

Insights

Nutritional status impacts drug metabolism. This study reveals that peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha mediates the fasting-induced expression of cytochrome P450 (CYP) 2A5 in mouse liver cells.

Area of Science:

  • Metabolism
  • Molecular Biology
  • Hepatology

Background:

  • Nutritional status and metabolic diseases affect xenobiotic metabolism.
  • Mechanisms regulating xenobiotic metabolism, particularly drug metabolism, are not fully understood.
  • Cytochrome P450 (CYP) 2A5, a key xenobiotic-metabolizing enzyme, is induced by fasting and cyclic AMP (cAMP).

Purpose of the Study:

  • To elucidate the regulatory mechanism of CYP2A5 induction during fasting.
  • To investigate the role of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha in mediating cAMP-induced CYP2A5 expression.

Main Methods:

  • Primary murine hepatocytes were used to study gene expression.
  • Adenovirus-mediated gene transfer was employed to manipulate PGC-1alpha levels.
  • Reporter gene assays and chromatin immunoprecipitation were performed to analyze gene regulation.

Main Results:

  • Cyclic AMP (cAMP) induced coordinated expression of PGC-1alpha and CYP2A5 mRNAs.
  • Increased PGC-1alpha expression enhanced CYP2A5 transcription.
  • PGC-1alpha activated CYP2A5 transcription via the hepatocyte nuclear factor (HNF)-4alpha response element.

Conclusions:

  • PGC-1alpha mediates cAMP-induced CYP2A5 expression in mouse hepatocytes.
  • PGC-1alpha coactivates the transcription factor HNF-4alpha to regulate CYP2A5.
  • PGC-1alpha is identified as a major mediator of the fasting response for CYP2A5.

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