Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats.

Vegard Lysne,Øivind Midttun,Gard Svingen,Eva Pedersen,Ottar Nygård,Rolf Berge,Elin Strand,Thomas Olsen,Bodil Bjørndal,Per Ueland

doi:10.3390/nu8010026

Vegard Lysne, Øivind Midttun + Show 8 more

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https://doi.org/10.3390/nu8010026

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Abstract

Plasma concentrations of metabolites along the choline oxidation pathway have been linked to increased risk of major lifestyle diseases, and peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of key enzymes along this pathway. In this study, we investigated the effect of PPAR activation on circulating and urinary one-carbon metabolites as well as markers of B-vitamin status. Male Wistar rats (n = 20) received for 50 weeks either a high-fat control diet or a high-fat diet with tetradecylthioacetic acid (TTA), a modified fatty acid and pan-PPAR agonist with high affinity towards PPARα. Hepatic gene expression of PPARα, PPARβ/δ and the enzymes involved in the choline oxidation pathway were analyzed and concentrations of metabolites were analyzed in plasma and urine. TTA treatment altered most biomarkers, and the largest effect sizes were observed for plasma concentrations of dimethylglycine, nicotinamide, methylnicotinamide, methylmalonic acid and pyridoxal, which were all higher in the TTA group (all p < 0.01). Hepatic Pparα mRNA was increased after TTA treatment, but genes of the choline oxidation pathway were not affected. Long-term TTA treatment was associated with pronounced alterations on the plasma and urinary concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats.

Highlights

Elevated plasma total homocysteine is related to increased risk of atherothrombotic cardiovascular disease (CVD) [1]
PPARα and these between elevated plasma risk may partly be related to enhanced endogenous pathways, and we previously suggested that the association between elevated plasmaPPARα risk may partly be related to enhanced endogenous PPARα activity [6,7]
This long-term, 50 weeks, animal study indicated that tetradecylthioacetic acid (TTA) treatment was associated with pronounced effects on the hepatic gene expression of PPARα and PPARβ/δ and on circulating concentrations of metabolites along the choline oxidation pathway and one-carbon metabolism as well as markers of B-vitamin status

Summary

Introduction

Elevated plasma total homocysteine (tHcy) is related to increased risk of atherothrombotic cardiovascular disease (CVD) [1]. Lowering of tHcy with B-vitamins has not improved prognosis among CVD patients [2], which is questioning a causal relationship and encourages investigation into novel mechanisms associated with elevated plasma tHcy [3]. Circulating and urinary concentrations of various metabolites along the choline oxidation pathway, which is linked to remethylation of Hcy, have been related to major lifestyle diseases including CVD and diabetes [4,5,6,7,8]. Nutrients 2016, 8, 26 increased risk of acute myocardial infarction as well as total and cardiovascular mortality, independent. Nutrients 2016, 8, x of traditional risk markers including elevated plasma tHcy [6,7].

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