GDF11 induces mild hepatic fibrosis independent of metabolic health

Jan Frohlich, Kristina Kovacovicova, Tommaso Mazza, Maria R. Emma, Daniela Cabibi, Michelangelo Foti, Cyril Sobolewski, Jude A. Oben, Marion Peyrou, Francesc Villarroya, Maurizio Soresi, Rita Rezzani, Melchiorre Cervello, Francesca Bonomini, Anna Alisi, Manlio Vinciguerra

Research output: Contribution to journalArticlepeer-review

Abstract

Background & aims: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Results: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARy and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. Conclusions: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. Methods: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).

Original languageEnglish
Pages (from-to)20024-20039
Number of pages16
JournalAging
Volume12
Issue number20
DOIs
Publication statusPublished - Oct 2020

Keywords

  • fibrosis
  • growth differentiation factor 11
  • liver
  • NAFLD
  • NASH

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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