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).

Anatomy and Physiopathology Division Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Bioinformatics Unit IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

CIBER Fisiopatología de la Obesidad y Nutrición Barcelona Catalonia Spain

Department of Biochemistry and Molecular Biomedicine Institute of Biomedicine of the University of Barcelona Barcelona Catalonia Spain

Department of Cell Physiology and Metabolism Faculty of Medicine University of Geneva Geneva Switzerland

Department of Health Promotion Sciences Maternal and Infantile Care Internal Medicine and Medical Specialties University of Palermo Palermo Italy

Institut de Recerca Hospital de la Santa Creu i Sant Pau Barcelona Catalonia Spain

Institute for Biomedical Research and Innovation National Research Council Palermo Italy

Institute for Liver and Digestive Health Division of Medicine University College London London United Kingdom

Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs University of Brescia Brescia Italy

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Research Area for Multifactorial Diseases Research Unit of Molecular Genetics of Complex Phenotypes Bambino Gesù Children's Hospital IRCCS Rome Italy

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