Cystathionine γ-Lyase Deficiency Exacerbates CCl₄-Induced Acute Hepatitis and Fibrosis in the Mouse Liver

Aims: The present study examined the role of cystathionine γ-lyase (CSE) in carbon tetrachloride (CCl₄)-induced liver damage.

Results: A CSE gene knock-out and luciferase gene knock-in (KI) mouse model was constructed to study the function of CSE and to trace its expression in living status. CCl₄ or lipopolysaccharide markedly downregulated CSE expression in the liver of mice. CSE-deficient mice showed increased serum alanine aminotransferase and aspartate aminotransferase levels, and liver damage after CCl₄ challenge, whereas albumin and endogenous hydrogen sulfide (H₂S) levels decreased significantly. CSE knockout mice showed increased serum homocysteine levels, upregulation of inflammatory cytokines, and increased autophagy and IκB-α degradation in the liver in response to CCl₄ treatment. The increase in pro-inflammatory cytokines, including tumor necrosis factor-alpha in CSE-deficient mice after CCl₄ challenge, was accompanied by a significant increase in liver tissue hydroxyproline and α-smooth muscle actin and histopathologic changes in the liver. However, H₂S donor pretreatment effectively attenuated most of these imbalances.

Innovation: Here, a CSE knock-out and luciferase KI mouse model was established for the first time to study the transcriptional regulation of CSE expression in real time in a non-invasive manner, providing information on the effects and potential mechanisms of CSE on CCl₄-induced liver injury.

Conclusion: CSE deficiency increases pro-inflammatory cytokines in the liver and exacerbates acute hepatitis and liver fibrosis by reducing H₂S production from L-cysteine in the liver. The present data suggest the potential of an H₂S donor for the treatment of liver diseases such as toxic hepatitis and fibrosis. Antioxid. Redox Signal. 27, 133-149.