Receptor‑interacting protein kinase‑1 ablation in liver parenchymal cells promotes liver fibrosis in murine NASH without affecting other symptoms

Autor: Muhammad Farooq, Mélanie Simoes Eugénio, Claire Piquet-Pellorce, Sarah Dion, Céline Raguenes-Nicol, Kathleen Santamaria, Ghania Hounana Kara-Ali, Thibaut Larcher, Marie-Thérèse Dimanche-Boitrel, Michel Samson, Jacques Le Seyec
Přispěvatelé: Institut National de la Santé et de la Recherche Médicale (INSERM), University of Veterinary and Animal Sciences [Lahore, Pakistan] (UVAS), EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Expertise en Anatomie Pathologique (APEX), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Contrat de Plan Etat Region' (CPER), Ligue Contre le Cancer, Comites du Grand Ouest, Biology and Health Federative Research Structure of Rennes (Biosit, UMS CNRS ) [3480/US INSERM 018], Fondation pour la Recherche Medicale (FRM ) [DEQ20180339216], Government of Pakistan (Higher Education Commission), Region Bretagne, Ministere de l'Enseignement Superieur et de la Recherche, Jonchère, Laurent
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Journal of Molecular Medicine
Journal of Molecular Medicine, 2022
HAL
Journal of Molecular Medicine, 2022, 100 (7), pp.1027-1038. ⟨10.1007/s00109-022-02192-5⟩
ISSN: 0946-2716
1432-1440
Popis: International audience; Non-alcoholic steatohepatitis (NASH), a chronic liver disease that emerged in industrialized countries, can further progress into liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the next decade, NASH is predicted to become the leading cause of liver transplantation, the only current interventional therapeutic option. Hepatocyte death, triggered by different death ligands, plays key role in its progression. Previously, we showed that the receptor-interacting protein kinase-1 (RIPK1) in hepatocytes exhibits a protective role in ligand-induced death. Now, to decipher the role of RIPK1 in NASH, Ripk1(LPC-KO) mice, deficient for RIPK1 only in liver parenchymal cells, and their wild-type littermates (Ripk1(fl/fl)) were fed for 3, 5, or 12 weeks with high-fat high-cholesterol diet (HFHCD). The main clinical signs of NASH were analyzed to compare the pathophysiological state established in mice. Most of the symptoms evolved similarly whatever the genotype, whether it was the increase in liver to body weight ratio, the steatosis grade or the worsening of liver damage revealed by serum transaminase levels. In parallel, inflammation markers followed the same kinetics with significant equivalent inductions of cytokines (hepatic mRNA levels and blood cytokine concentrations) and a main peak of hepatic infiltration of immune cells at 3 weeks of HFHCD. Despite this identical inflammatory response, more hepatic fibrosis was significantly evidenced at week 12 in Ripk1(LPC-KO) mice. This coincided with over-induced rates of transcripts of genes implied in fibrosis development (Tgfb1, Tgfbi, Timp1, and Timp2) in Ripk1(LPC-KO) animals. In conclusion, our results show that RIPK1 in hepatocyte limits the progression of liver fibrosis during NASH.
Databáze: OpenAIRE
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