Inhibition of glutathione generation in hepatic steatotic rats augments oxidative stress

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 gamma-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.

Automated summary

This study investigated the restoration of glutathione (GSH) deficiency induced by an inhibitor of gamma-glutamyl cysteine synthetase (BSO) through the administration of GSH ester. It was found that mice fed a diet with cholesterol and sodium cholate developed fatty liver disease accompanied by reduced GSH levels. Additionally, the combination of BSO and fatty liver disease resulted in even lower GSH levels. Further analysis indicated that BSO plus fatty liver disease led to cholesterol accumulation, decreased antioxidant enzyme activity, increased reactive oxygen species (ROS) levels, elevated blood glucose, and abnormal plasma lipid profile. However, the administration of GSH ester prevented GSH depletion, increased antioxidant enzyme activity, reduced ROS levels, and restored plasma lipid concentration. Histopathological analysis also revealed that GSH ester administration ameliorated inflammation and hepatocyte ballooning. In conclusion, this study suggests that restoring GSH levels through GSH ester injection plays a crucial role in delaying the progression of fatty liver disease.