Inhibition of glutathione generation in hepatic steatotic rats augments oxidative stress

Abstract

Fatty liver disease has been strongly associated with a low glutathione (GSH) level in hepatocytes with increased oxidative stress, which is critically involved in the initiation and progression of the disease. The study investigated whether the GSH deficiency induced by buthionine sulfoximine (BSO), an inhibitor of γ-glutamyl cysteine synthetase, can be restored by the administration of GSH ester. We showed that mice fed a diet with cholesterol plus sodium cholate developed steatosis followed by hepatic GSH reduction. Moreover, the GSH level in the cytosol and mitochondria of steatosis plus BSO decreased than that of steatosis alone. Subsequent studies with the liver tissues and plasma of BSO plus steatosis revealed the accumulation of cholesterol in the hepatocytes, downregulating the concentration of GSH, antioxidant enzymes, and GSH metabolizing enzymes with a significant rise in reactive oxygen species (ROS), blood glucose level and plasma lipid profile. The administration of GSH ester in BSO-administered mice, prevented the depletion of GSH by upregulating the GSH concentration, antioxidant enzymes, and GSH metabolizing enzymes, followed by a reduction in ROS and plasma lipid concentration. The histopathological analysis showed a marked increase in inflammation followed by hepatocytes ballooning in BSO-induced group and steatosis control group, which was ameliorated by GSH ester administration. In conclusion, our data suggest that the restoration of GSH in the cytosol and mitochondria through the injection with GSH ester plays a principal role in maintaining the GSH level in the liver, thereby delaying the progression of fatty liver disease.

Keywords:

• Mitochondria
• buthionine sulfoximine
• glutathione ester
• lipid peroxidation
• antioxidants
• liver

Acknowledgments

The authors duly acknowledge the funding support from UGC, India, in the form of MRP (F. No. 37-308/2009 (SR), dated 12 January 2010) and Department of Science and Technology (DST-FIST), New Delhi, India. The first author also acknowledges the UGC, India for the University Fellowship.

Author contributions

K.S. and T.K.: data curation and drafting the manuscript; N.S.: performed animal experiment, assays, and data analysis; C.T.: fundamental conception of the study, supervision, manuscript editing, and proofreading.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Upon request data will be shared.

Additional information

Funding

This research received funding from UGC, India.