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

Huma Hameed, Muhammad Farooq, Céline Vuillier, Claire Piquet-Pellorce, Annaïg Hamon, Marie Thérèse Dimanche-Boitrel, Michel Samson*, Jacques Le Seyec

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 dam-age. 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 devel-oped 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 sur-vival. 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.

Original languageEnglish
Article number7367
JournalInternational Journal of Molecular Sciences
Volume23
Issue number13
DOIs
Publication statusPublished - Jul 1 2022
Externally publishedYes

Keywords

  • acute hepatitis
  • apoptosis
  • carbon tetrachloride
  • drug-induced liver injury
  • receptor-interacting protein kinase-1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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