Thyromimetic mode of action of peroxisome proliferators: activation of ‘malic’ enzyme gene transcription

Abstract

Peroxisome proliferators induce thyroid-hormone-dependent liver activities, e.g. ‘malic’ enzyme, mitochondrial glycerol-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, S14 [Hertz, Aurbach, Hashimoto and Bar-Tana (1991) Biochem. J. 274, 745–751]. Here we report that the thyromimetic effect of peroxisome proliferators with respect to ‘malic’ enzyme results from transcriptional activation of the ‘malic’ enzyme gene, mediated by binding of the peroxisome proliferator activated receptor (PPARα)/retinoid X receptor (RXRα) heterodimer to a 5´-flanking enhancer of the ‘malic’ enzyme promoter. The enhancer involved is distinct from the thyroid hormone response element of the ‘malic’ enzyme promoter and is partly homologous with that which mediates transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisome proliferators. Hence transcriptional activation of thyroid-hormone-dependent liver genes by xenobiotic or endogenous amphipathic carboxylates collectively defined as peroxisome proliferators is mediated by a transduction pathway similar to that involved in transcriptional activation of peroxisomal β-oxidative genes and distinct from that which mediates thyroid hormone action.