Peroxisome proliferators-activated receptor α controls tryptophan-NAD metabolism in rodents

Abstract

The effect of peroxisome-proliferators (PPs) on tryptophan (Trp)-NAD metabolism in rodents was investigated. Administration of PPs increased NAD levels in primary cultured rat hepatocytes. The time course for the NAD increase was similar to the expression of the nuclear receptor PPARα and its target genes. To determine the relationship between PPARα and the increase in NAD levels after PP administration, PPARα-null (−/−) and wild type (+/+) mice were examined. ACOX was up-regulated in +/+ mice by the potent PPARα ligand Wy-14,643 (Wy), but not in −/− mice. The α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase gene (ACMSD) was down-regulated by Wy in +/+ mice and up-regulated in −/− mice compared with +/+ mice. Depending on the ligand, PPARα activation down-regulated expression of ACMSD directly or indirectly. The increase in hepatic NAD levels by Wy was observed in +/+ mice, but not in −/− mice. The contribution of altered ACMSD expression to NAD levels was determined. PPARα agonists affected Trp-NAD metabolism in rodents through PPARα-related gene expression resulting in altered hepatic NAD levels that promote fatty acid β-oxidation. Trp-NAD metabolism may also be influenced by PPARα activation by endogenous ligands.