Abstract
We showed recently that a targeted null mutation in the murine sterol carrier protein 2-/sterol carrier protein x-gene (Scp2) leads to defective peroxisomal catabolism of 3,7,11, 15-tetramethylhexadecanoic acid (phytanic acid), peroxisome proliferation, hypolipidemia, and enhanced hepatic expression of several genes that have been demonstrated to be transcriptionally regulated by the peroxisome proliferator-activated receptor alpha (PPARalpha). As a broad range of fatty acids activates PPARalpha in vitro, we examined whether the latter effects could be because of phytanic acid-induced activation of this transcription factor. Dietary phytol supplementation was used to modulate the concentration of phytanic acid in C57Bl/6 and Scp2 (-/-) mice. We found that the serum concentrations of phytanic acid correlated well with the expression of genes encoding peroxisomal beta-oxidation enzymes and liver fatty acid-binding protein, which have all been demonstrated to contain functionally active peroxisome proliferator response elements in their promoter regions. In accordance with these findings, a stimulating effect on acyl-CoA oxidase gene expression was also observed after incubation of the rat hepatoma cell line MH1C1 with phytanic acid. Moreover, reporter gene studies revealed that phytanic acid induces the expression of a peroxisome proliferator response element-driven chloramphenicol transferase reporter gene comparable with strong peroxisome proliferators. In addition, the ability of phytanic acid to act as an inductor of PPARalpha-dependent gene expression corresponded with high affinity binding of this dietary branched chain fatty acid to recombinant PPARalpha. We conclude that phytanic acid can be considered as a bona fide physiological ligand of murine PPARalpha.
Highlights
Apart from serving as fuels in energy metabolism, fatty acids have been proposed to act as regulators in gene expression
We demonstrated recently that the loss of the sterol carrier protein 2-/sterol carrier protein x-gene (Scp2) gene function led to drastically elevated phytanic acid serum concentrations accompanied by peroxisome proliferation, hypolipidemia, impaired body weight control, neuropathy, and markedly altered hepatic gene expression (14)
The most drastic induction was evident in the high phytol Scp2 (Ϫ/Ϫ) group in whom expression was between five- and more than 10-fold higher than in the low phytol C57Bl/6 group
Summary
Apart from serving as fuels in energy metabolism, fatty acids have been proposed to act as regulators in gene expression (reviewed in Ref. 1). Important roles in this process have been assigned to heterodimers consisting of peroxisome proliferator-. The phenotype of the SCP2/SCPx knockout mouse, Scp (Ϫ/Ϫ), did not provide evidence for a role of the gene in intracellular cholesterol trafficking but revealed instead defective peroxisomal degradation of certain natural methyl-branched fatty acyl-CoAs such as phytanic and pristanic acid, which are metabolized in peroxisomes. We demonstrate that phytanic acid does bind to recombinant PPAR␣ and induces the expression of a PPRE-driven CAT reporter gene comparable with strong peroxisome proliferators. The identification of phytanic acid as a bona fide physiological ligand of PPAR␣ is of special interest, as an accumulation of this dietary fatty acid is observed in Scp (Ϫ/Ϫ) mice and in several inherited human diseases, e.g. Refsum disease and Zellweger syndrome (21)
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