Branched-Chain Fatty Acids as Mediators of the Activation of Hepatic Peroxisome Proliferator-Activated Receptor Alpha by a Fungal Lipid Extract.

Garima Maheshwari,Marco A Fraatz,Johanna Rost,Robert Ringseis,Denise K Gessner,Klaus Eder,Holger Zorn,Gaiping Wen

doi:10.3390/biom10091259

Abstract

The study aimed to test the hypothesis that monomethyl branched-chain fatty acids (BCFAs) and a lipid extract of Conidiobolus heterosporus (CHLE), rich in monomethyl BCFAs, are able to activate the nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha). Rat Fao cells were incubated with the monomethyl BCFAs 12-methyltridecanoic acid (MTriA), 12-methyltetradecanoic acid (MTA), isopalmitic acid (IPA) and 14-methylhexadecanoic acid (MHD), and the direct activation of PPARalpha was evaluated by reporter gene assay using a PPARalpha responsive reporter gene. Furthermore, Fao cells were incubated with different concentrations of the CHLE and PPARalpha activation was also evaluated by using the reporter gene assay, and by determining the mRNA concentrations of selected PPARalpha target genes by real-time RT-PCR. The reporter gene assay revealed that IPA and the CHLE, but not MTriA, MHD and MTA, activate the PPARalpha responsive reporter gene. CHLE dose-dependently increased mRNA concentrations of the PPARalpha target genes acyl-CoA oxidase (ACOX1), cytochrome P450 4A1 (CYP4A1), carnitine palmitoyltransferase 1A (CPT1A) and solute carrier family 22 (organic cation/carnitine transporter), member 5 (SLC22A5). In conclusion, the monomethyl BCFA IPA is a potent PPARalpha activator. CHLE activates PPARalpha-dependent gene expression in Fao cells, an effect that is possibly mediated by IPA.

Highlights

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor that belongs to the superfamily of nuclear hormone receptors and is predominantly expressed in tissues with high rates of fatty acid oxidation
Rat Fao cells were incubated with the monomethyl Branched-chain fatty acids (BCFAs) 12-methyltridecanoic acid (MTriA), 12-methyltetradecanoic acid (MTA), isopalmitic acid (IPA) and 14-methylhexadecanoic acid (MHD), and the direct activation of PPARalpha was evaluated by reporter gene assay using a PPARalpha responsive reporter gene
Using a PPARalpha-responsive reporter gene, we studied the effect of CHLE and isolated fatty acids contained in the CHLE on PPARalpha transactivation

Summary

Introduction

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor that belongs to the superfamily of nuclear hormone receptors and is predominantly expressed in tissues with high rates of fatty acid oxidation. Apart from the abovementioned PPARalpha activators, the tetramethyl branched-chain, isoprenoid-derived fatty acids phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) and pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) as well as their CoA-thioesters were shown to be high-affinity natural ligands and potent activators of PPARalpha [7,8,9,10]. As early as 1967, Tyrrell described the composition of fatty acids in various species of the fungal genus Conidiobolus and reported proportions of BCFAs of up to 73% of total fatty acids [17]. Whether these monomethyl BCFAs are able to activate PPARalpha, is currently unknown

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Conclusion