TY - JOUR
T1 - Receptor-interacting protein kinase-1 ablation in liver parenchymal cells promotes liver fibrosis in murine NASH without affecting other symptoms
AU - Farooq, Muhammad
AU - Simoes Eugénio, Mélanie
AU - Piquet-Pellorce, Claire
AU - Dion, Sarah
AU - Raguenes-Nicol, Céline
AU - Santamaria, Kathleen
AU - Kara-Ali, Ghania Hounana
AU - Larcher, Thibaut
AU - Dimanche-Boitrel, Marie Thérèse
AU - Samson, Michel
AU - Le Seyec, Jacques
N1 - Funding Information:
This work was supported by the “Contrat de Plan Etat-Région” (CPER) grant named “Infectio”; the “Ligue Contre le Cancer, Comités du Grand Ouest”; the Biology and Health Federative Research Structure of Rennes (Biosit, UMS CNRS 3480/US INSERM 018) and the “Fondation pour la Recherche Médicale” (FRM # DEQ20180339216). M.F. was supported by a PhD fellowship from the Government of Pakistan (Higher Education Commission). M.S.E. was supported by a PhD fellowship from “Région Bretagne” and “Ministère de l’Enseignement Supérieur et de la Recherche.” G.H.K.A. was supported by a PhD fellowship from “Ministère de l’Enseignement Supérieur et de la Recherche.”
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022
Y1 - 2022
N2 - 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, Ripk1LPC−KO mice, deficient for RIPK1 only in liver parenchymal cells, and their wild-type littermates (Ripk1fl/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 Ripk1LPC−KO mice. This coincided with over-induced rates of transcripts of genes implied in fibrosis development (Tgfb1, Tgfbi, Timp1, and Timp2) in Ripk1LPC−KO animals. In conclusion, our results show that RIPK1 in hepatocyte limits the progression of liver fibrosis during NASH.
AB - 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, Ripk1LPC−KO mice, deficient for RIPK1 only in liver parenchymal cells, and their wild-type littermates (Ripk1fl/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 Ripk1LPC−KO mice. This coincided with over-induced rates of transcripts of genes implied in fibrosis development (Tgfb1, Tgfbi, Timp1, and Timp2) in Ripk1LPC−KO animals. In conclusion, our results show that RIPK1 in hepatocyte limits the progression of liver fibrosis during NASH.
KW - Fibrosis
KW - Hepatocyte
KW - NASH
KW - RIPK1
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U2 - 10.1007/s00109-022-02192-5
DO - 10.1007/s00109-022-02192-5
M3 - Article
C2 - 35476028
AN - SCOPUS:85128815510
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
ER -