Pristanic acid is activator of peroxisome proliferator activated receptor alpha

Abstract

lsoprenoid phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is degraded in peroxisomes by α-oxidation to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) and then via β-oxidation. Branched-chain phytanic acid is an activator of the peroxisome proliferator activated receptor α (PPAR ) which in liver cells regulates expression of genes encoding peroxisomal and mitochondrial β-oxidative enzymes as well as cytosolic/nuclear liver-type fatty acid binding protein (L-FABP). In this report we address the question whether pristanic acid also acts as activator of PPARα and thus mediates the expression of its catabolizing enzymes. In a first in vivo approach we fed pristanic acid for 14 days to wildtype mice and to mice lacking sterol carrier protein 2/sterol carrier protein x which Ieads to a phenotype having high concentrations of branched-chain fatty acids. In either genotype, feeding pristanic acid was associated with a strong induction of peroxisomal β-oxidation enzymes tested (acyl-CoA oxidase, bifunctional enzyme, thiolase) as well as of L-FABP. The link between pristanic acid and protein expression observed was established by carrying out assays for transactivation of PPARα in transfected HepG2 cells. In comparison to hypolipidemic drugs and to straight-chain fatty acids known to be PPARα agonists, branched-chain phytanic and pristanic acids were substantially stronger activators, pristanic acid being even superior to phytanic acid.