GDF11 induces mild hepatic fibrosis independent of metabolic health.
Adult
Animals
Bone Morphogenetic Proteins
/ genetics
Case-Control Studies
Cell Line
Disease Progression
Female
Growth Differentiation Factors
/ genetics
Hepatic Stellate Cells
/ metabolism
Humans
Liver
/ metabolism
Liver Cirrhosis
/ diagnosis
Liver Cirrhosis, Experimental
/ chemically induced
Male
Mice, Inbred C57BL
Middle Aged
Non-alcoholic Fatty Liver Disease
/ diagnosis
Obesity, Morbid
/ complications
Signal Transduction
NAFLD
NASH
fibrosis
growth differentiation factor 11
liver
Journal
Aging
ISSN: 1945-4589
Titre abrégé: Aging (Albany NY)
Pays: United States
ID NLM: 101508617
Informations de publication
Date de publication:
28 10 2020
28 10 2020
Historique:
received:
31
07
2020
accepted:
25
08
2020
pubmed:
31
10
2020
medline:
20
4
2021
entrez:
30
10
2020
Statut:
ppublish
Résumé
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). 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. GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. 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).
Sections du résumé
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).
Identifiants
pubmed: 33126224
pii: 104182
doi: 10.18632/aging.104182
pmc: PMC7655202
doi:
Substances chimiques
Bone Morphogenetic Proteins
0
GDF11 protein, human
0
Growth Differentiation Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20024-20046Références
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