6533b858fe1ef96bd12b5b6e

RESEARCH PRODUCT

GDF11 induces mild hepatic fibrosis independent of metabolic health

Marion PeyrouMaurizio SoresiJan FrohlichTommaso MazzaMaria Rita EmmaAnna AlisiFrancesca BonominiMelchiorre CervelloManlio VinciguerraDaniela CabibiMichelangelo FotiKristina KovacovicovaCyril SobolewskiRita RezzaniFrancesc VillarroyaJude A. Oben

subject

Liver CirrhosisMaleAgingSettore MED/09 - Medicina Interna*liverLiver Cirrhosis ExperimentalFetgeWeight lossFibrosisfibrosis; growth differentiation factor 11; liver; NAFLD; NASHNon-alcoholic Fatty Liver DiseaseGrowth differentiation factor 11Fatty liverNASH*fibrosisMiddle AgedObesity MorbidGrowth Differentiation FactorsLiverBone Morphogenetic ProteinsDisease ProgressionFemalemedicine.symptomResearch PaperSignal TransductionAdultmedicine.medical_specialtygrowth differentiation factor 11Inflammationliverdigestive systemCell LineEnvellimentInternal medicineNAFLDmedicineHepatic Stellate CellsAnimalsHumansddc:612*growth differentiation factor 11business.industry*NAFLDfibrosisnutritional and metabolic diseasesCell Biologyliver NAFLD NASH fibrosis growth differentiation factor 11*NASHmedicine.diseaseFibrosisdigestive system diseasesMice Inbred C57BLEndocrinologyPortal fibrosisCase-Control StudiesGDF11Hepatic stellate cellSteatohepatitisHepatic fibrosisbusiness

description

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, PPAR? 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).

yearjournalcountryeditionlanguage
2020-10-28
10.18632/aging.104182http://hdl.handle.net/10447/447208