Glutathione deficiency down-regulates hepatic lipogenesis in rats.
BACKGROUND
Oxidative stress is supposed to increase lipid accumulation by stimulation of hepatic lipogenesis at transcriptional level. This study was performed to investigate the role of glutathione in the regulation of this process. For that purpose, male rats were treated with buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, for 7 days and compared with untreated control rats.


RESULTS
BSO treatment caused a significant reduction of total glutathione in liver (-70%), which was attributable to diminished levels of reduced glutathione (GSH, -71%). Glutathione-deficient rats had lower triglyceride concentrations in their livers than the control rats (-23%), whereas the circulating triglycerides and the cholesterol concentrations in plasma and liver were not different between the two groups of rats. Livers of glutathione-deficient rats had lower mRNA abundance of sterol regulatory element-binding protein (SREBP)-1c (-47%), Spot (S)14 (-29%) and diacylglycerol acyltransferase 2 (DGAT-2, -27%) and a lower enzyme activity of fatty acid synthase (FAS, -26%) than livers of the control rats. Glutathione-deficient rats had also a lower hepatic activity of the redox-sensitive protein-tyrosine phosphatase (PTP)1B, and a higher concentration of irreversible oxidized PTP1B than control rats. No differences were observed in protein expression of total PTP1B and the mature mRNA encoding active XBP1s, a key regulator of unfolded protein and ER stress response.


CONCLUSIONS
This study shows that glutathione deficiency lowers hepatic triglyceride concentrations via influencing lipogenesis. The reduced activity of PTP1B and the higher concentration of irreversible oxidized PTP1B could be, at least in part, responsible for this effect.
Brandsch
Corinna
C
Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Von-Danckelmann-Platz 2, D-06120 Halle (Saale), Germany.
Schmidt
Tobias
T
Behn
Diana
D
Weisse
Kristin
K
Mueller
Andreas S
AS
Stangl
Gabriele I
GI
D000818:Animals; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005978:Glutathione / Q000172:deficiency*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014280:Triglycerides / Q000097:blood
D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D019328:Buthionine Sulfoximine; D002784:Cholesterol; D017027:Protein Tyrosine Phosphatases; D005978:Glutathione