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 journalArticleResearchpeer-review

6 Citations (Scopus)

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 Fmr1 null 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-FLIP S and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1 null 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
Pages (from-to)133-145
Number of pages13
JournalGut
Volume69
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

Keywords

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

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