Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury

Yuan Zhuang, Haifeng C. Xu, Prashant V. Shinde, Jens Warfsmann, Jelena Vasilevska, Balamurugan Sundaram, Kristina Behnke, Jun Huang, Jessica I. Hoell, Arndt Borkhardt, Klaus Pfeffer, Mohamed S. Taha, Diran Herebian, Ertan Mayatepek, Dirk Brenner, Mohammad Reza Ahmadian, Verena Keitel, Dagmar Wieczorek, Dieter Häussinger, Aleksandra A. PandyraKarl S. Lang, Philipp A. Lang*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Objective: The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease. Design: Mice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry. Results: Fmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1null mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL. Conclusions: We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.

Original languageEnglish
JournalGut
Volume69
Issue number1
Pages (from-to)133-145
ISSN0017-5749
DOIs
Publication statusPublished - Jan 2020

Keywords

  • Fragile X syndrome
  • liver damage
  • septic shock
  • TNF receptor signaling

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