Role of Fn14 in acute alcoholic steatohepatitis in mice
Autor: | Marzena Swiderska-Syn, Gregory A. Michelotti, Steve S. Choi, Anna Mae Diehl, Cynthia A. Moylan, Mariana Verdelho Machado, Guanhua Xie, Cynthia D. Guy, Gamze Karaca, Linda C. Burkly, Leandi Krüger |
---|---|
Rok vydání: | 2014 |
Předmět: |
Male
medicine.medical_specialty Programmed cell death Time Factors Physiology Inflammation Apoptosis Biology Receptors Tumor Necrosis Factor Fibrosis Liver Cirrhosis Alcoholic Physiology (medical) Internal medicine medicine Animals Progenitor cell Carbon Tetrachloride Cell Proliferation Liver injury Mice Knockout Wound Healing Hepatology Ethanol Tumor Necrosis Factor-alpha Gastroenterology medicine.disease Mice Inbred C57BL Disease Models Animal Hydroxyproline Liver and Biliary Tract Endocrinology medicine.anatomical_structure Liver TWEAK Receptor Hepatocyte Immunology Acute Disease Tumor necrosis factor alpha medicine.symptom Inflammation Mediators Fatty Liver Alcoholic Signal Transduction |
Zdroj: | American journal of physiology. Gastrointestinal and liver physiology. 308(4) |
ISSN: | 1522-1547 |
Popis: | TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14+ progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure. |
Databáze: | OpenAIRE |
Externí odkaz: |