Phytanic acid, a natural peroxisome proliferator‐activated receptor agonist, regulates glucose metabolism in rat primary hepatocytes

Abstract

Phytanic acid, a metabolite of the chlorophyll molecule, is part of the human diet and is present in normal human serum at low micromolar concentrations. It was previously shown to be a ligand of the 9-cis-retinoic acid receptor and peroxisome proliferator-activated receptor (PPAR) a. PPAR agonists are widely used in the treatment of type 2 diabetes. Here, we report that phytanic acid is not only a transactivator of PPARa, but it also acts via PPARb and PPARg in CV-1 cells that have been cotransfected with the respective full-length receptor and an acyl-CoA oxidase-PPAR-responsive element-luciferase construct. We observed that, in contrast to other fatty acids, phytanic acid at physiological concentrations enhances uptake of 2-deoxy-D-glucose in rat primary hepatocytes. This result could be explained by the increase in mRNA expression of glucose transporters-1 and -2 and glucokinase, as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Compared with the PPARg-specific agonist ciglitazone, phytanic acid exerts only minor effects on the differentiation of C3H10T1/2 cells into mature adipocytes. These results clearly demonstrate that phytanic acid acts via different PPAR isoforms to modulate expression of genes involved in glucose metabolism, thus suggesting a potential role of phytanic acid in the management of insulin resistance.

IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells

“…The subcellular localization of IDH1 in both cytosol and peroxisomes ideally situates it to respond to the lipogenic requirement of the cell. The coproduct of the reaction, ␣-ketoglutarate, which is required as a cosubstrate for the phytanoyl-CoA ␣-hydroxylase reaction (17)(18)(19)(20), is required for the catabolic removal of phytanic acid, a known agonist to PPAR␣ (21,22). PPAR␣ is highly expressed in heart, muscle, kidney, and endothelial cells, but mostly in liver (27,34), where its function is in the catabolism of fatty acids through the regulation of genes encoding mitochondrial and peroxisomal enzymes important for ␤-oxidation (68).…”

“…Several metabolic functions for phytanic acid have been reported: regulation of glucose metabolism in primary rat hepatocytes by acting as an agonist to peroxisome proliferator-activated receptors (PPARs) (21,22) and retinoid X receptor (RXR) (23); white adipocyte differentiation (24); and activation of uncoupling protein-1 gene transcription and brown adipocyte differentiation (25). In the autosomal disorder Refsum's disease, ␣ -oxidation of phytanic acid is affected in some, but not all, cases, and accumulation of this acid is observed in various tissues (26).…”

Fractionation and identification of 9c, 11t, 13t-conjugated linolenic acid as an activator of PPARα in bitter gourd (Momordica charantia L.)

“…A number of PPARs activators that are of food/diet origin have been identified. Conjugated linoleic acids [25] and phytanic acid [12] are well-known examples of which health benefits have been demonstrated. The hypolipidemic effect of fish oil [8] has been attributed, at least in part, to the activation of PPARa.…”

Fatty acid composition evaluation of edible parts of Eriocheir sinensis in intensive ponds of Gucheng waters

“…A previous study showed that phytanic acid had cytotoxic effects on the mitochondria and stellate cells in the rat brain (Schönfeld et al, 2006). However, both phytanic and pristane acids play a regulatory role in adipocyte differentiation and polyester, glucose, and lipid metabolism (Heim, 2002); it can promote fatty acid b-oxidation and significantly lower liver triglyceride and plasma fatty acids (Gloerich et al, 2007). In this study, both commercial pellet feed-feeding and small trash fish-feeding crabs contained high levels of phytanic acid, suggesting that crab is similar to other high phytanic acid foods and may have potential health functions.…”