Pristanic acid is activator of peroxisome proliferator activated receptor alpha

Abstract

Pristanic acid is activator of peroxisome proliferator activated receptor alpha 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 (PPARα) 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.

Naissance d’une fédération

“…This was indeed the case as can be seen first in the upper part of Figure 4, which demonstrates that at fixed intracellular L-FABP concentration linoleic acid afforded a dose dependent enhancement of PPARalpha trans-activation. The lower part of Figure 4 reveals not only that increased L-FABP content in the cells led to increased transactivation, but also that phytanic acid is a very potent agonists for transactivation [9,27]. In accordance with our data it was shown by others that L-FABP enters the nucleus when loaded with fatty acids [39], which corroborates its function as a carrier for fatty acid signaling molecules to their respective nuclear receptors.…”

“…Of the natural ligands straight-chain fatty acids, with few exceptions, all bind and transactivate all PPAR isoforms. Interestingly, branched-chain phytanic acid binds and transactivates PPARalpha but not PPARgamma while pristanic acid was shown to be a potent activator of PPARalpha as well [9,27]. Thus isoprenoid branched-chain fatty acids appear to interact solely with the alpha isoform of PPARs for high potency induction of enzymes.…”

“…In this model system phytanic and pristanic acids where the most potent natural transactivators (Figure 3) [27,28].…”

Phytanic acid—an overlooked bioactive fatty acid in dairy fat?

“…It is also noteworthy that the product of α‐oxidation of phytanic, pristanic acid, is a considerable more efficient PPAR‐α agonist than phytanic acid itself. It has been described as the most potent PPAR‐α agonist, among the naturally occurring fatty acids 26,27,29 . Zomer and colleagues show that pristanic acid efficiently activates PPAR‐α in the low micromolar range 26 .…”

“…Because of the prohibitive high price of phytanic acid, there are no data on intervention with pure phytanic acid in either animal or human studies, while one feeding study with pristanic acid has been published (see below) 29 . Hence, the physiological effects of phytanic acid have solely been studied in cell models or through intervention with its metabolic precursor, phytol.…”