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 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 (Thr(172)Ala) and kinase-less (Asp(157)Ala, Asp(139)Ala) mutants of AMPKalpha. The Ser(452) Ala mutant of mPPARalpha mutated in its putative consensus AMPKalpha phosphorylation site is similarly co-activated by AMPKalpha. AMPKa or its kinase-less mutants bind to PPARa; 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 PPARa 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 AMPKa or its kinase-less mutants to the cytosol. In conclusion, AMPKa, independently of its kinase activity, coactivates PPARalpha both in primary rat hepatocytes and in PPARalpha-transfected cells. The kinase and transcriptional co-activation modes of AMPKa are both regulated by the cellular ATP/AMP ratio. Co-activation of PPARalpha by AMPKalpha may transcriptionally complement AMPK in maintaining cellular ATP status.