Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor α

Abstract

Phytanic acid and pristanic acid are branchedchain fatty acids, present at micromolar concentrations in the plasma of healthy individuals. Here we show that both phytanic acid and pristanic acid activate the peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) in a concentrationdependent manner. Activation is observed via the ligandbinding domain of PPAR ␣ as well as via a PPAR response element (PPRE). Via the PPRE significant induction is found with both phytanic acid and pristanic acid at concentrations of 3 and 1 M, respectively. The trans -activation of PPAR ␦ and PPAR ␥ by these two ligands is negligible. Besides PPAR ␣ , phytanic acid also trans -activates all three retinoic X receptor subtypes in a concentration-dependent manner. In primary human fibroblasts, deficient in phytanic acid ␣ -oxidation, trans -activation through PPAR ␣ by phytanic acid is observed. This clearly demonstrates that phytanic acid itself, and not only its metabolite, pristanic acid, is a true physiological ligand for PPAR ␣ . Because induction of PPAR ␣ occurs at ligand concentrations comparable to the levels found for phytanic acid and pristanic acid in human plasma, these fatty acids should be seen as naturally occurring ligands for PPAR ␣ . These results demonstrate that both pristanic acid and phytanic acid are naturally occurring ligands for PPAR ␣ , which are present at physiological concentrations. -Zomer, A. W. M., B. van der Burg, G. A. Jansen, R. J. A. Wanders, B. T. Poll-The, and P. T. van der Saag. Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferatoractivated receptor ␣ .

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

“…Previous reports showed that omega-3 eicosapentaenoic acid (20:5, ω3) and, to a lesser extent, docosahexaenoic acid (22:6, ω3), are potent ligands [96,97] and consistent activators of PPARα [98][99][100], while omega-3 PUFA like linolenic acid (C18:3, ω3) and docosapentaenoic (22:5, ω3) acids, and omega-6 PUFA such as linoleic (C18:2, ω6) and arachidonic (C20:4, ω6) acids are weaker PPARα activators [74,99,100]. In addition, experiments performed by Ellinghaus et al and Zomer et al [101,102] revealed that phytanic acid (3,7,11,15-tertamethylhexadecanoic acid) is a strong natural physiological ligand for PPARα. These assumptions were then followed by reports from Hostetler et al [103], showing that PPARα binds the fatty acyl-CoAs (3-20 nM Kds) and branched-chain fatty acyl-CoA (BCFA-CoAs, phytanoyl-CoA, pristanoyl-CoA; Kds near 11 nM) with the highest affinities (i.e., Kd at nM range).…”

RXR – centralny regulator wielu ścieżek sygnałowych w organizmie

“…Obie struktury różnią się istotnie, głównie pod względem innego położenia helisy H12. C. Krótka charakterystyka funkcjonalna dla poszczególnych regionów/ domen RXR; wg [53,54,55,56] najbardziej złożonym fragmentem receptora pod względem funkcjonalnym. Zawiera sekwencję odpowiedzialną za zależną od liganda aktywację transkrypcji (AF2, activation function 2), ponadto jest zaangażowany w niezależną od DNA dimeryzację, oddziaływanie z koregulatorami oraz często w nieobecności liganda pośredniczy w represji transkrypcji [35].…”

“…w mięsie przeżuwaczy i wyrobach mleczarskich. Kwas fitanowy odpowiada głównie za aktywację homodimerów RXR [83], choć może pełnić również rolę liganda PPAR [56]. Kwas fitanowy aktywuje RXR w stężeniu 10 µM.…”

Slc25a17 Gene Trapped Mice: PMP34 Plays a Role in the Peroxisomal Degradation of Phytanic and Pristanic Acid

“…In addition to hepatocytes with cytosolic catalase, the EM pictures showed cells with increased number of peroxisomes and with enlarged peroxisomes, likely the result of increased PPARα activation. The accumulating phytol breakdown products, phytanic and pristanic acid, can indeed activate PPARα and possibly other transcription factors as well (Kitareewan et al, 1996;Zomer et al, 2000). Enlarged peroxisomes have been described in at least two other mouse models for peroxisomal protein deficiencies, such as the PMP70 (ABCD3) KO mouse (Jimenez-Sanchez et al, 2000) and the phytol fed AMACR KO mouse (Savolainen et al, 2004).…”