Role of Fn14 in acute alcoholic steatohepatitis in mice.

Journal Article (Journal Article)

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 CClâ‚„ for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CClâ‚„ 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.

Full Text

Duke Authors

Cited Authors

  • Karaca, G; Xie, G; Moylan, C; Swiderska-Syn, M; Guy, CD; Krüger, L; Machado, MV; Choi, SS; Michelotti, GA; Burkly, LC; Diehl, AM

Published Date

  • February 15, 2015

Published In

Volume / Issue

  • 308 / 4

Start / End Page

  • G325 - G334

PubMed ID

  • 25524063

Pubmed Central ID

  • PMC4329478

Electronic International Standard Serial Number (EISSN)

  • 1522-1547

Digital Object Identifier (DOI)

  • 10.1152/ajpgi.00429.2013


  • eng

Conference Location

  • United States