Abstract
BackgroundOxidative 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 γ-glutamylcysteine synthetase, for 7 days and compared with untreated control rats.ResultsBSO 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.ConclusionThis 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.
Highlights
Oxidative stress is supposed to increase lipid accumulation by stimulation of hepatic lipogenesis at transcriptional level
Lipid synthesis was investigated at the transcriptional level by the analysis of the mRNA expression of Sterol regulatory element-binding protein (SREBP)-1c, the key transcription factor involved in the stimulation of lipogenesis in the liver [18,19], and of related enzymes involved in lipid synthesis and at the activity level by analysis of lipogenic enzymes fatty acid synthase (FAS) and glucose-6-phosphate dehydrogenase (G6PDH)
We further investigated the activity of the transcription factor X-box binding protein (XPB)1 that has been identified as a key regulator of the mammalian unfolded protein response as well as a stimulator of hepatic lipogenesis [26] and the inositol-requiring enzyme (IRE)-1 that transforms the XBP1 mRNA in its active form (XBP1s) by splicing
Summary
Oxidative stress is supposed to increase lipid accumulation by stimulation of hepatic lipogenesis at transcriptional level. Pro-oxidants and many pathological conditions such as inflammatory liver diseases, diabetes and hyperglycemia are accompanied by reduced intracellular levels of glutathione [13,14,15], the effect of inhibited glutathione synthesis as a model for endogenously produced oxidative stress on lipogenesis is not yet well understood. This study investigated the effect of glutathione depletion on lipid concentrations in plasma and liver, on expression of genes and activities of enzymes involved in lipid synthesis. Lipid synthesis was investigated at the transcriptional level by the analysis of the mRNA expression of SREBP-1c, the key transcription factor involved in the stimulation of lipogenesis in the liver [18,19], and of related enzymes involved in lipid synthesis and at the activity level by analysis of lipogenic enzymes FAS and G6PDH
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