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Effects of WY-14,643 on the phosphorylation and activation of AMP-dependent protein kinase

Suthat Liangpunsakul1, Sung-Eun Wou, Kevin D Wineinger

  • 1Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, 545 N. Barnhill Drive, Indianapolis, IN 46202, USA.

Archives of Biochemistry and Biophysics
|February 25, 2009
PubMed
Abstract

Insights

WY-14,643, a PPARalpha agonist, increases AMP-dependent protein kinase (AMPK) activity and phosphorylation in liver cells. This study investigates the mechanism behind this activation, finding it independent of upstream kinases and AMP:ATP ratio changes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hepatology

Background:

  • AMP-dependent protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) alpha are key regulators of fatty acid oxidation.
  • Ethanol treatment inhibits both PPARalpha and AMPK activity, contributing to fatty liver.
  • WY-14,643, a PPARalpha agonist, has previously shown efficacy in reversing alcohol-induced fatty liver.

Purpose of the Study:

  • To investigate the effect of WY-14,643 on AMPK activity and phosphorylation.
  • To explore the underlying mechanisms of WY-14,643-induced AMPK activation.

Main Methods:

  • Examined the impact of WY-14,643 on AMPK phosphorylation and activity in H4IIEC3 rat hepatoma cells.
  • Assessed the influence of WY-14,643 on upstream kinases (PKC-zeta/LKB1), intracellular AMP:ATP ratio, oxidative stress, and AMPK gene expression.

Main Results:

  • WY-14,643 treatment increased AMPK phosphorylation by 60% in H4IIEC3 cells.
  • Activation was independent of PKC-zeta/LKB1 and did not alter AMP:ATP ratio or reactive oxygen species levels.
  • WY-14,643 induced AMPK alpha subunit mRNA expression (2- to 2.5-fold) but not protein levels at 24 hours.

Conclusions:

  • WY-14,643 treatment stimulates AMPK phosphorylation and activity in liver cells.
  • This activation is linked to increased AMPKalpha1 and alpha2 mRNA expression.
  • The precise mechanism driving WY-14,643-mediated AMPK activation remains to be fully elucidated.

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