No abstract

No abstract

No abstract

Metabolic switching of oxidative fuel use from glucose and three-carbon compounds to fatty acids is a key adaptive mechanism to maintain blood glucose levels during starvation [1,2]. To limit the irreversible decarboxylation of pyruvate to acetyl-CoA, pyruvate dehydrogenase kinases (PDKs) are induced by starvation and phosphorylate the pyruvate dehydrogenase complex that catalyzes decarboxylation. Of four isoforms, PDK4 has been reported to be the most highly inducible [3]. It is known that PDK4 is induced in the liver and muscles of mice by fasting [4,5] and also by the administration of a peroxisome proliferator-activated receptor a (PPARa) ligand [6].We reported previously that hypolipidemic drug fibrates, PPARa ligands, rapidly induce PDK4 mRNA in various mouse tissues [7]. This is in stark contrast to the relatively slow induction of the mRNAs for fatty acid utilization which are mostly limited to the liver. The observation that fibrates rapidly and efficiently induced mRNA at the whole-body level prompted us to propose a metabolic-switching hypothesis as the first step in the hypolipidemic effect of fibrates. Rapid and general inactivation of the pyruvate dehydrogenase complex by fibrate-induced PDK4 is followed by metabolic switching to limit oxidative fuel to fatty acids, thus enhancing fatty acid utilization. This is the driving force for fatty acid uptake from the blood, and uptake is further accelerated by induction of the enzymes involved in fatty acid utilization and repression of the inhibitor apoCIII for fatty acid-producing Pyruvate dehydrogenase kinase 4 (PDK4) is a key regulatory enzyme involved in switching the energy source from glucose to fatty acids in response to physiological conditions. Transcription of the PDK4 gene is activated by fasting or by the administration of a PPARa ligand in a tissue-specific manner. Here, we show that the two mechanisms are independent, and that ERRa is directly involved in PPARa-independent transcriptional activation of the PDK4 gene with PGC-1a as a specific partner. This conclusion is based on the following evidence. First, detailed mutation analyses of the cloned PDK4 gene promoter sequence identified a possible ERRa-binding motif as the PGC-1a responsive element. Second, overexpression of ERRa by cotransfection enhanced, and the knockout of it by shRNAs diminished, PGC-1a-dependent activation. Third, specific binding of ERRa to the identified PGC-1a responsive sequence was confirmed by the electrophoresis mobility shift assay. Finally, cell-type-specific responsiveness to PGC-1a was observed and this could be explained by differences in the expression levels of ERRa, however, ectopic expression of ERRa in poorly responsive cells did not restore PGC-1a responsiveness, indicating that ERRa is necessary, but not sufficient for the response.Abbreviations DMEM, Dulbecco's modified Eagle's medium; ERRa, estrogen related receptor a; FOXO, forkhead box class O; GFP, green fluorescent protein; GR, glucocorticoid receptor; PDK, pyruvate dehydrogenase kinase; PDK4,...