Kinase-independent transcriptional co-activation of peroxisome proliferator-activated receptor alpha by AMP-activated protein kinase

Biochem J. 2004 Dec 1;384(Pt 2):295-305. doi: 10.1042/BJ20040955.

Abstract

AMPK (AMP-activated protein kinase) responds to intracellular ATP depletion, while PPARalpha (peroxisome proliferator-activated receptor alpha) induces the expression of genes coding for enzymes and proteins involved in increasing cellular ATP yields. PPARalpha-mediated transcription is shown here to be co-activated by the alpha subunit of AMPK, as well as by kinase-deficient (Thr172Ala) and kinase-less (Asp157Ala, Asp139Ala) mutants of AMPKalpha. The Ser452Ala mutant of mPPARalpha mutated in its putative consensus AMPKalpha phosphorylation site is similarly co-activated by AMPKalpha. AMPKalpha or its kinase-less mutants bind to PPARalpha; binding is increased by MgATP, to a lesser extent by MgADP, but not at all by AMP or ZMP [AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) monophosphate]. ATP-activated binding of AMPKalpha to PPARalpha is mediated primarily by the C-terminal regulatory domain of AMPKalpha. PPARalpha co-activation by AMPKalpha may, however, require its secondary interaction with the N-terminal catalytic domain of AMPKalpha, independently of its kinase activity. While AMPK catalytic activity is activated by AICAR, PPARalpha co-activation and PPARalpha-controlled transcription are robustly inhibited by AICAR, with concomitant translocation of nuclear AMPKalpha or its kinase-less mutants to the cytosol. In conclusion, AMPKalpha, independently of its kinase activity, co-activates PPARalpha both in primary rat hepatocytes and in PPARalpha-transfected cells. The kinase and transcriptional co-activation modes of AMPKalpha are both regulated by the cellular ATP/AMP ratio. Co-activation of PPARalpha by AMPKalpha may transcriptionally complement AMPK in maintaining cellular ATP status.

MeSH terms

  • AMP-Activated Protein Kinases
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • COS Cells / chemistry
  • COS Cells / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Chlorocebus aethiops
  • HeLa Cells / chemistry
  • HeLa Cells / metabolism
  • Hepatocytes / chemistry
  • Hepatocytes / metabolism
  • Humans
  • Kidney / cytology
  • Kidney / embryology
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Multienzyme Complexes / physiology*
  • PPAR alpha / genetics*
  • PPAR alpha / metabolism
  • Phosphotransferases / metabolism*
  • Protein Subunits / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Rats
  • Ribonucleotides / pharmacology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • Transfection

Substances

  • Multienzyme Complexes
  • PPAR alpha
  • Protein Subunits
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Phosphotransferases
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide