Glutathione defense mechanism in liver injury: Insights from animal models

Abstract

Glutathione (GSH) is the most abundant cellular thiol antioxidant and it exhibits numerous and versatile functions. Disturbances in GSH homeostasis have been associated with liver diseases induced by drugs, alcohol, diet and environmental pollutants. Until recently, our laboratories and others have developed mouse models with genetic deficiencies in glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the GSH biosynthetic pathway. This review focuses on regulation of GSH homeostasis and, specifically, recent studies that have utilized such GSH-deficient mouse models to investigate the role of GSH in liver disease processes. These studies have revealed a differential hepatic response to distinct profiles of hepatic cellular GSH concentration. In particular, mice engineered to not express the catalytic subunit of GCL in hepatocytes [Gclc(h/h) mice] experience almost complete loss of hepatic GSH (to 5% of normal) and develop spontaneous liver pathologies characteristic of various clinical stages of liver injury. In contrast, mice globally engineered to not express the modifier subunit of GCL [Gclm(−/−) mice] show a less severe hepatic GSH deficit (to ≈15% of normal) and exhibit overall protection against liver injuries induced by a variety of hepatic insults. Collectively, these transgenic mouse models provide interesting new insights regarding pathophysiological functions of GSH in the liver.

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

“…Glutathione is a thiol-containing tripeptide that serves as a major endogenous nonenzymatic antioxidant against oxidative stress [14, 15]. The liver has high glutathione levels due to its efficient synthesis [14–18]. Impaired liver function and metabolism have been found in animal models with ischemic AKI [19–22].…”

Metabolism of Sulfur-Containing Amino Acids in the Liver: A Link between Hepatic Injury and Recovery

“…17) There is increasing evidence that dysregulation of GSH synthesis contributes to the pathogenesis of many liver diseases including non-alcoholic fatty liver disease, alcoholic liver disease, and drug-induced liver injury. 18) GSH synthesis is mediated by glutamate cysteine ligase (GCL), which is composed of a catalytic (GCLC) and a modifier (GCLM) subunit, and GSH synthase (GS), which catalyze consecutive reactions. The major factors affecting GSH synthesis are the availability of the substrate, cysteine, and the activity of GCL, which is the rate-limiting enzyme.…”

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

“…Oxidative stress is a common pathogenic factor in most liver diseases, including chronic hepatitis C virus (HCV) infection, as well as alcoholic and non-alcoholic fatty liver disease [1-3]. Parenchymal cells, mainly represented by hepatocytes, are primarily subjected to oxidative stress and are able to induce injury in other non-parenchymal cells such as hepatic stellate cells (HSCs) and endothelial cells, which are very sensitive to oxidative stress-related molecules.…”