THYROMIMETIC MODE OF ACTION OF PEROXISOME PROLIFERATORS - ACTIVATION OF MALIC ENZYME GENE-TRANSCRIPTION

Peroxisome proliferators induce thyroid-hormone-dependent liver activi ties, e.g. 'malic' enzyme, mitochondrial glycerol-3-phosphate dehydrog enase, glucose-6-phosphate dehydrogenase, S14 [Hertz, Aurbach, Hashimo to and Bar-Tana (1991) Biochem. J. 274, 745-751]. Here we report that the thyromimetic effect of peroxisome proliferators with respect to 'm alic' enzyme results from transcriptional activation of the 'malic' en zyme gene, mediated by binding of the peroxisome proliferator activate d receptor (PPAR alpha)/retinoid X receptor (RXR alpha) heterodimer to a 5'-flanking enhancer of the 'malic' enzyme promoter. The enhancer i nvolved is distinct from the thyroid hormone response element of the ' malic' enzyme promoter and is partly homologous with that which mediat es transcriptional activation of peroxisomal acyl-CoA oxidase by perox isome proliferators. Hence transcriptional activation of thyroid-hormo ne-dependent liver genes by xenobiotic or endogenous amphipathic carbo xylates collectively defined as peroxisome proliferators is mediated b y a transduction pathway similar to that involved in transcriptional a ctivation of peroxisomal beta-oxidative genes and distinct from that w hich mediates thyroid hormone action.