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

Myriam Bronner, Rachel Hertz, Jacob Bar-Tana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

AMPK (AMP-activated protein kinase) responds to intracellular ATP depletion, while PPARα (peroxisome proliferator-activated receptor a) induces the expression of genes coding for enzymes and proteins involved in increasing cellular ATP yields. PPARα-mediated transcription is shown here to be co-activated by the α subunit of AMPK, as well as by kinase-deficient (Thr172Ala) and kinase-less (Asp157Ala, Asp139Ala) mutants of AMPKα. The Ser452Ala mutant of mPPARα mutated in its putative consensus AMPKα phosphorylation site is similarly co-activated by AMPKα. AMPKα or its kinase-less mutants bind to PPARα; 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 AMPKα to PPARα is mediated primarily by the C-terminal regulatory domain of AMPKα. PPARα co-activation by AMPKα may, however, require its secondary interaction with the N-terminal catalytic domain of AMPKα, independently of its kinase activity. While AMPK catalytic activity is activated by AICAR, PPARα co-activation and PPARα-controlled transcription are robustly inhibited by AICAR, with concomitant translocation of nuclear AMPKα or its kinase-less mutants to the cytosol. In conclusion, AMPKα, independently of its kinase activity, co-activates PPARα both in primary rat hepatocytes and in PPARα-transfected cells. The kinase and transcriptional co-activation modes of AMPKα are both regulated by the cellular ATP/AMP ratio. Co-activation of PPARα by AMPKα may transcriptionally complement AMPK in maintaining cellular ATP status.

Original languageEnglish
Pages (from-to)295-305
Number of pages11
JournalBiochemical Journal
Volume384
Issue number2
DOIs
StatePublished - 1 Dec 2004

Keywords

  • 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)
  • AMP-activated protein kinase (AMPK)
  • ATP/AMP ratio
  • Nuclear translocation
  • Peroxisome proliferator-activated receptor α (PPARα)
  • Transcription

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