RIPK1 in Liver Parenchymal Cells Limits Murine Hepatitis during Acute CCl4-Induced Liver Injury.

Abstract

Some life-threatening acute hepatitis originates from drug-induced liver injury (DILI). Carbon tetrachloride (CCl4)-induced acute liver injury in mice is the widely used model of choice to study acute DILI, which pathogenesis involves a complex interplay of oxidative stress, necrosis, and apoptosis. Since the receptor interacting protein kinase-1 (RIPK1) is able to direct cell fate towards survival or death, it may potentially affect the pathological process of xenobiotic-induced liver damage. Two different mouse lines, either deficient for Ripk1 specifically in liver parenchymal cells (Ripk1LPC-KO) or for the kinase activity of RIPK1 (Ripk1K45A, kinase dead), plus their respective wild-type littermates (Ripk1fl/fl, Ripk1wt/wt), were exposed to single toxic doses of CCl4. This exposure led in similar injury in Ripk1K45A mice and their littermate controls. However, Ripk1LPC-KO mice developed more severe symptoms with massive hepatocyte apoptosis as compared to their littermate controls. A pretreatment with a TNF-α receptor decoy exacerbated liver apoptosis in both Ripk1fl/fl and Ripk1LPC-KO mice. Besides, a FasL antagonist promoted hepatocyte apoptosis in Ripk1fl/fl mice but reduced it in Ripk1LPC-KO mice. Thus, the scaffolding properties of RIPK1 protect hepatocytes from apoptosis during CCl4 intoxication. TNF-α and FasL emerged as factors promoting hepatocyte survival. These protective effects appeared to be independent of RIPK1, at least in part, for TNF-α, but dependent on RIPK1 for FasL. These new data complete the deciphering of the molecular mechanisms involved in DILI in the context of research on their prevention or cure.

• Authors: Huma Hameed, Muhammad Farooq, Céline Vuillier, Claire Piquet-Pellorce, Annaïg Hamon, Marie-Thérèse Dimanche-Boitrel, Michel Samson, Jacques Le Seyec
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 13 (Jul 01 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35806372 (Publication Type: Journal Article)

Chemical References

• Tumor Necrosis Factor-alpha
• Carbon Tetrachloride
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse

Topics

• Animals
• Apoptosis
• Carbon Tetrachloride (toxicity)
• Chemical and Drug Induced Liver Injury (metabolism)
• Chemical and Drug Induced Liver Injury, Chronic (metabolism)
• Hepatitis (metabolism)
• Hepatocytes (metabolism)
• Liver (metabolism)
• Mice
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)