Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice

J Pharmacol Exp Ther. 2012 May;341(2):307-16. doi: 10.1124/jpet.111.189340. Epub 2012 Jan 23.


Macrophages play an integral role in the development of liver fibrosis by releasing mediators, such as platelet-derived growth factor-B (PDGF-B) and transforming growth factor-β1, which stimulate hepatic stellate cell proliferation, chemotaxis, and collagen production. However, the mechanism by which chronic liver injury stimulates macrophages to release these mediators is not completely understood. We tested the hypothesis that chronic liver injury activates hypoxia-inducible factor (HIF) transcription factors in macrophages that regulate the production of mediators that promote fibrosis. To test this hypothesis, Cre/lox technology was used to generate myeloid cell-specific HIF-1α or HIF-1β knockout mice. When these mice were subjected to bile duct ligation (BDL), levels of α-smooth muscle actin and type I collagen in the liver were reduced compared with those of mice with normal levels of HIFs. The deficiency of HIFs in macrophages did not affect liver injury or inflammation after BDL but reduced PDGF-B mRNA and protein, suggesting that HIF activation in macrophages may promote fibrosis by regulating the production of PDGF-B. Consistent with a role for HIFs in liver fibrosis in cholestatic liver disease, nuclear HIF-1α protein was present in macrophages, hepatocytes, and fibroblasts in the livers from patients with primary biliary cirrhosis and primary sclerosing cholangitis. These studies demonstrate that HIFs are important regulators of profibrotic mediator production by macrophages during the development of liver fibrosis and suggest that HIFs may be a novel therapeutic target for the treatment of chronic liver disease in patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Adult
  • Aged
  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • Bile Ducts / metabolism
  • Cell Hypoxia / physiology
  • Cholestasis / genetics
  • Cholestasis / metabolism
  • Cholestasis / pathology*
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Female
  • Fibroblasts / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Kupffer Cells / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology
  • Proto-Oncogene Proteins c-sis / genetics
  • Proto-Oncogene Proteins c-sis / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation / genetics


  • Actins
  • Arnt protein, mouse
  • Collagen Type I
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins c-sis
  • Transcription Factors
  • alpha-smooth muscle actin, mouse
  • Aryl Hydrocarbon Receptor Nuclear Translocator