Role of PPARα in the regulation of glutathione metabolism

Abstract

Glutathione (GSH) derives from cysteine and plays a key role in redox status. GSH synthesis is determined by the availability of cysteine (from the diet or derived from methionine) and by the activity of rate limiting enzyme glutamyl‐cysteine synthase (GCS). Because PPARα has been shown to regulate the secondary metabolism of certain amino acids, GSH synthesis from cysteine was explored in fasted wild‐type (WT) and PPARα‐null (KO) male mice, fed on a semi synthetic standard diet. The concentration of plasma amino acids and of hepatic thiols was measured. Activity and mRNA levels of GCS were determined in the liver.Plasma cysteine concentration was identical in both groups, whereas that of methionine was 18% higher in KO mice. Hepatic GSH concentration was 40% higher in KO mice, whereas other thiols (cysteine, homocysteine and cysteinylglycine) were not affected. GCS activity of KO mice was 16% higher for specific activity and 52% higher for total hepatic activity.In contrast, PPARα deficiency did not affect GCS mRNA level. In conclusion, PPARα deficiency enhanced hepatic GSH storage, probably through an increased synthesis from cysteine. Thus, PPARα may influence the redox status by regulating cysteine metabolism. However, the absence of transcriptional regulation of GCS suggests a more complex control of GSH synthesis. Research support: Valorex & GLN (France).