1. Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.
- Author
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Gehrke N, Nagel M, Straub BK, Wörns MA, Schuchmann M, Galle PR, and Schattenberg JM
- Subjects
- Animals, Apoptosis, Bile Acids and Salts metabolism, Bile Acids and Salts toxicity, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Cells, Cultured, Choledocholithiasis etiology, Choledocholithiasis genetics, Choledocholithiasis pathology, Cytokines metabolism, Genetic Predisposition to Disease, Hepatic Stellate Cells drug effects, Hepatic Stellate Cells pathology, Hepatitis etiology, Hepatitis genetics, Hepatitis pathology, Hepatocytes drug effects, Hepatocytes pathology, Inflammation Mediators metabolism, Ligation, Liver drug effects, Liver pathology, Liver Cirrhosis etiology, Liver Cirrhosis genetics, Liver Cirrhosis pathology, Mice, Knockout, Necrosis, Neutrophil Infiltration, Oxidative Stress, Phenotype, Signal Transduction, Time Factors, Transcription Factor RelA metabolism, Tumor Necrosis Factor alpha-Induced Protein 3 metabolism, p38 Mitogen-Activated Protein Kinases metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein deficiency, Choledocholithiasis metabolism, Common Bile Duct surgery, Hepatic Stellate Cells metabolism, Hepatitis metabolism, Hepatocytes metabolism, Liver metabolism, Liver Cirrhosis metabolism
- Abstract
Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP
-/- ) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP-/- mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP-/- mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.- Published
- 2018
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