In a previous study of male Wistar rats, we demonstrated that long-term treatment with the pan-PPAR agonist tetradecylthioacetic acid (TTA) was associated with alteration in the plasma concentration of several metabolites along the choline oxidation pathway as well as markers of B-vitamin status. Increased urinary output of NAM and mNAM have been consistently reported in rodents. Reduced folate has also been reported in humans by some, but not all.
PPARα activation in animals have also been linked to altered status of several B-vitamins, such as increased plasma concentrations of riboflavin, nicotinamide (NAM) and N 1-methylnicotinamide (mNAM), the vitamin B6 indices pyridoxal (PL) and pyridoxal-5’-phosphate (PLP) and the functional marker of cobalamin deficiency, methylmalonic acid (MMA), and reduced plasma folate. In animals, PPARα activation has been associated with increased plasma DMG as well as increased glycine and serine. Treatment of humans with fibrates, which are PPARα agonists, have consistently been associated with increased plasma total homocysteine (tHcy), and also decreased plasma betaine concentrations and increased urinary output of choline, betaine and DMG. Down regulation on the protein level of BHMT, DMGDH, SARDH and GNMT have also been observed in rats and mice.
Down regulation of the genes encoding DMG dehydrogenase (DMGDH), sarcosine dehydrogenase (SARDH) and glycine-N-methyltransferase (GNMT) of the choline oxidation pathway, as well as both enzymes of the transsulfuration pathway, have been observed after PPARα activation in rats. Recent studies in animals have implicated PPARs, in particular the PPARα subtype, in the regulation of one-carbon metabolism pathways. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors involved in the regulation of a variety of metabolic functions, including different aspects of energy metabolism. DMG indicates dimethylglycine Hcy, homocysteine Met, methionine mTHF, 5’-methyltetrahydrofolate and THF, tetrahydrofolate. The figure indicates where the enzymatic reactions occur (within/outside mitocondria). The numbers indicate enzymes, and the black boxes indicate enzymes of which gene expression have been previously shown to be down regulated by PPARα activation. Overview of metabolic pathways discussed. Plasma and urinary concentration of metabolites in this pathway, including choline, betaine, DMG, sarcosine, glycine and serine, have been linked to risk of major lifestyle diseases such as diabetes, cancer and cardiovascular disease. Alternatively to remethylation, homocysteine may be irreversibly catabolized through the transsulfuration pathway, by the enzymes cystathionine-β-synthase and cystathionine-γ-lyase ( Fig 1). The other homocysteine remethylation pathway is catalyzed by methionine synthase (MS), where the methyl group is transferred from 5’-methyltetrahydrofolate (mTHF) via the MS bound cofactor methylcobalamin (vitamin B12) forming methionine. In this reaction a methyl group is transferred from betaine to homocysteine, producing methionine and DMG. The choline oxidation pathway is closely related to the homocysteine-methionine cycle, through the enzyme betaine-homocysteine methyl transferase (BHMT). Glycine may also be reversibly synthesized from serine via serine-hydroxymethyltransferase. The choline oxidation pathway consists of the metabolic reactions converting choline, originating from endogenous synthesis or from the diet, to glycine via the intermediate metabolites betaine, dimethylglycine (DMG) and sarcosine.
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