PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal

Nature. 2015 Jun 25;522(7557):474-7. doi: 10.1038/nature14326. Epub 2015 May 11.


Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Disease
  • Anemia / drug therapy
  • Anemia / metabolism
  • Anemia / pathology
  • Anemia, Hemolytic / metabolism
  • Animals
  • Butyrates / pharmacology
  • Butyrates / therapeutic use
  • Cell Culture Techniques
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chronic Disease
  • Disease Models, Animal
  • Erythroid Precursor Cells / cytology*
  • Erythroid Precursor Cells / drug effects
  • Erythroid Precursor Cells / metabolism
  • Erythropoiesis* / drug effects
  • Erythropoietin / pharmacology
  • Female
  • Fenofibrate / pharmacology
  • Glucocorticoids / pharmacology
  • Humans
  • Liver / cytology
  • Liver / drug effects
  • Liver / embryology
  • Mice
  • PPAR alpha / agonists
  • PPAR alpha / deficiency
  • PPAR alpha / metabolism*
  • Phenylhydrazines / pharmacology
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use
  • Receptors, Glucocorticoid / metabolism*
  • Signal Transduction / drug effects


  • Butyrates
  • Chromatin
  • GW 7647
  • Glucocorticoids
  • PPAR alpha
  • Phenylhydrazines
  • Phenylurea Compounds
  • Receptors, Glucocorticoid
  • phenylhydrazine
  • Erythropoietin
  • Fenofibrate

Associated data

  • GEO/GSE63836
  • GEO/GSE63837