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 almostcomplete 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.

Keywords: Glutamate-cysteine ligase; Glutathione; Liver injury; Oxidative stress; Steatohepatitis; Steatosis.

Figure 1. Pathways for glutathione (GSH) biosynthesis, transport and metabolism

Details of these pathways are discussed in the text. Cys, L-cysteine; Glu, L-glutamate; Gly, L-glycine; DP, dipeptidase; GCL, glutamate-cysteine ligase; GGT, γ-glutamyltransferase; GSS, glutathione synthase; GSH, glutathione; GSSG, glutathione disulfide; ER, endoplasmic reticulum; MT, mitochondrion; NU, nucleus. Pink boxes represent catalytic enzymes; grey boxes represent transporters.

Figure 2. Schematic summary of observations from GSH-deficient mouse models

Studies in hepatocyte-specific Gclc(h/h) mice indicate that: (i) minimal levels of hepatic GSH (5% normal) are required for normal liver function, primarily by preserving mitochondrial functional integrity; and (ii) partial restoration of mitochondrial function by N-acetylcysteine (NAC) signals the induction of hepatic regeneration. In Gclm(−/−) KO mice in which the hepatic GSH deficit is less severe (15% normal) and chronic, mitochondrial function remains intact; metabolic and stress response adaptions protect these animals from steatosis and hepatic injuries induced by a variety of insults. Collectively, these studies show a differential hepatic response to GSH depletion, depending on the extent of depletion and nature of the insults. Molecular mechanism(s) underlying such GSH-mediated effects remain(s) to be elucidated.