Research Paper|Volume 12, Issue 20|pp 20024—20046

GDF11 induces mild hepatic fibrosis independent of metabolic health

Jan Frohlich¹, Kristina Kovacovicova¹, Tommaso Mazza², Maria R. Emma³, Daniela Cabibi⁴, Michelangelo Foti⁵, Cyril Sobolewski⁵, Jude A. Oben⁶, Marion Peyrou^7,⁸, Francesc Villarroya^7,^8,⁹, Maurizio Soresi⁴, Rita Rezzani^10,¹¹, Melchiorre Cervello³, Francesca Bonomini^10,¹¹, Anna Alisi¹², Manlio Vinciguerra^1,⁶

¹International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
²Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
³Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
⁴Department of Health Promotion Sciences, Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
⁵Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
⁶Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom
⁷Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Catalonia, Spain
⁸Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain
⁹CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Catalonia, Spain
¹⁰Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
¹¹Interdepartmental University Center of Research “Adaption and Regeneration of Tissues and Organs-(ARTO)”, University of Brescia, Brescia, Italy
¹²Research Area for Multifactorial Diseases, Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

* Equal contribution

Received: July 31, 2020Accepted: August 25, 2020Published: October 28, 2020

https://doi.org/10.18632/aging.104182

Copyright: © 2020 Frohlich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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, PPARγ 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).