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

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.