Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Transl Res. 2015 Feb;165(2):346-57. doi: 10.1016/j.trsl.2014.10.003. Epub 2014 Oct 13.


We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl4). Mice in treatment groups received CCl4 5 μL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of Van Gieson and α-smooth muscle actin (α-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-β, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl4-induced liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Carbon Tetrachloride / toxicity
  • Collagen / genetics
  • Cytokines / genetics
  • Disease Progression
  • Gene Expression / drug effects
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / physiopathology
  • Lung Injury / drug therapy
  • Lung Injury / pathology
  • Lung Injury / physiopathology
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Melatonin / physiology
  • Melatonin / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Translational Research, Biomedical


  • Actins
  • Cytokines
  • RNA, Messenger
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • alpha-smooth muscle actin, mouse
  • Collagen
  • Carbon Tetrachloride
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • Melatonin