TY - JOUR
T1 - GDF11 induces mild hepatic fibrosis independent of metabolic health
AU - Frohlich, Jan
AU - Kovacovicova, Kristina
AU - Mazza, Tommaso
AU - Emma, Maria R.
AU - Cabibi, Daniela
AU - Foti, Michelangelo
AU - Sobolewski, Cyril
AU - Oben, Jude A.
AU - Peyrou, Marion
AU - Villarroya, Francesc
AU - Soresi, Maurizio
AU - Rezzani, Rita
AU - Cervello, Melchiorre
AU - Bonomini, Francesca
AU - Alisi, Anna
AU - Vinciguerra, Manlio
N1 - Funding Information:
This work was supported by the European Social Fund and European Regional Development Fund - Project MAGNET (No. CZ.02.1.01/0.0/0.0/15_003/0000492, to M.V.), by the Associazione Italiana per la Ricerca sul Cancro (AIRC; No. 18394, to M.C.), and by the Swiss National Science Foundation (Grant no. 310030-172862 to M.F.).
Publisher Copyright:
© 2020 Frohlich et al.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - 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).
AB - 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).
KW - fibrosis
KW - growth differentiation factor 11
KW - liver
KW - NAFLD
KW - NASH
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U2 - 10.18632/aging.104182
DO - 10.18632/aging.104182
M3 - Article
C2 - 33126224
AN - SCOPUS:85092205916
VL - 12
SP - 20024
EP - 20039
JO - Aging
JF - Aging
SN - 1945-4589
IS - 20
ER -