GDF11 induces mild hepatic fibrosis independent of metabolic health

Aging (Albany NY). 2020 Oct 28;12(20):20024-20046. doi: 10.18632/aging.104182. Epub 2020 Oct 28.


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).

Keywords: NAFLD; NASH; fibrosis; growth differentiation factor 11; liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / toxicity
  • Case-Control Studies
  • Cell Line
  • Disease Progression
  • Female
  • Growth Differentiation Factors / genetics
  • Growth Differentiation Factors / metabolism*
  • Growth Differentiation Factors / toxicity
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Humans
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis, Experimental / chemically induced
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / diagnosis
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Obesity, Morbid / complications
  • Obesity, Morbid / diagnosis
  • Signal Transduction


  • Bone Morphogenetic Proteins
  • GDF11 protein, human
  • Growth Differentiation Factors