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 result from transcriptional activation of the 'malic' enzyme gene, mediated by binding of the peroxisome proliferator activated receptor (PPAR alpha)/retinoid X receptor (RXR alpha) 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 beta-oxidative genes and distinct from that which mediates thyroid hormone action.

Protein Profiling of Mouse Livers with Peroxisome Proliferator-Activated Receptor α Activation

“…For the 10 others, an association with peroxisome proliferation had not been demonstrated previously. The up-regulation of NADP-dependent malic enzyme in Wy-14,643-treated mice appeared similar to that reported previously (19,35). However, this regulation was not seen in the AOX Ϫ/Ϫ mice.…”

“…Levels of 6 of these 15 proteins were also significantly different between AOX Ϫ/Ϫ and Wy-14,643-treated mice, indicating the divergence of AOX gene disruption. Arginase 1 (liver type) (21), Cpsase I (21), fructose-1,6-bisphosphatase (22), mitochondrial aspartate aminotransferase (30), and NADP-dependent malic enzyme (19,35) have previously been shown to be regulated in livers with peroxisome proliferation. For the 10 others, an association with peroxisome proliferation had not been demonstrated previously.…”

The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates

“…Indeed, in rodents peroxisome proliferators and thyroid hormones often regulate the same target genes (49). In addition, certain of these genes have been shown to carry both TREs and PPREs (50,51). Cross-talk between PPAR and TR may furthermore occur by competition for binding to DNA (52,53) or for the common heterodimeric partner RXR (53)(54)(55)(56), or by formation of PPAR:TR heterodimers, as has been suggested by one report (57).…”

Nutraceutical Importance of Sesame Seed and Oil: A Review of the Contribution of their Lignans

“…Sesamin also increases the activity and gene expression of the malic enzyme involved in the regulation of fatty acid synthesis. The gene of malic enzyme, like that of many fatty acid oxidation enzymes possesses a peroxisome proliferator response element in the promoter (Hertz et al, 1996). The responses of the activity and gene expression of this enzyme may reflect the activation by sesamin of PPAR.…”