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Role of RIPK1 in the survival and death of hepatocytes : its involvement in murine hepatitis models

Abstract : Cell death plays central role in the development and progression of liver diseases. Irrespective of the etiological agents, it results in hepatocyte destruction, leading to inflammation and compensatory proliferation. In addition, the persistent cell demise can lead into fibrosis and ultimately hepatocellular carcinoma, the 3rd leading cause of cancer related death. Expression or release of death ligands, such as TNF-α, FAS L and TRAIL, by inflammatory cells remains the key players in the progression of liver diseases. Downstream of death ligand receptors or PAMPs, receptor interacting protein kinase 1 (RIPK1) influences the fate of cell, whether to survive or to die by caspase-dependent apoptosis or by RIPK3/MLKL-dependent necroptosis and could therefore be potential targets in regulating cell death. RIPK1 can have distinct pro-death or pro-survival role, regulated by its kinase or scaffolding functions, respectively. In line with this, we have already shown the protective role of RIPK1 in animal models of acute hepatitis induced by ConA, LPS. In my PhD work, the objective was to assess the role of RIPK1 in animal models of acute (fulminant viral hepatitis, CCl4 and acetaminophen [APAP] induced liver damage) and chronic hepatitis (High Fat High Cholesterol diet [HFHCD]-induced NASH). Our results demonstrated that RIPK1 protects hepatocytes from TNF-α secreted from macrophages during viral induced fulminant hepatitis. These data emphasize the potential worsening risks of an HBV infection in people with polymorphism or homozygous amorphic mutations already described for the RIPK1 gene. Besides, we established that RIPK1 in liver parenchymal cells does not influence APAP-induced liver injury in mice. Additional inhibition of RIPK1 kinase activity in Ripk1LPC-KO mice did not improve hepatic damage, revealing that RIPK1 kinase activity in liver non-parenchymal cells does not contribute to APAP-induced liver injury. Otherwise, we demonstrated that RIPK1 of liver parenchymal cells partly preserves the liver from CCl4-induced damage, lesions that do not depend on TNF-α . Finally, we showed that RIPK1 in liver parenchymal cells has a tendency to protect from HFHCD-induced fibrosis in murine NASH and that dietary intervention can improve liver fibrosis in mice with NASH. As for the role of RIPK1-kinase activity in NASH, it remains to be explored to evaluate its therapeutic interest.
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Submitted on : Tuesday, February 23, 2021 - 1:01:29 AM
Last modification on : Wednesday, February 24, 2021 - 2:57:05 PM

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Muhammad Farooq. Role of RIPK1 in the survival and death of hepatocytes : its involvement in murine hepatitis models. Microbiology and Parasitology. Université Rennes 1, 2019. English. ⟨NNT : 2019REN1B006⟩. ⟨tel-03149368⟩

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