Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice.
The role of retinoic acid (RA) in liver fibrogenesis was previously studied in cultured hepatic stellate cells (HSCs). RA suppresses the expression of alpha2(I) collagen by means of the activities of specific nuclear receptors RARalpha, RXRbeta and their coregulators. In this study, the effects of RA in fibrogenesis were examined in carbon tetrachloride (CCl4) induced liver fibrosis in mice. Mice were treated with CCl4 or RA and CCl4, along side control groups, for 12weeks. RA reduced the amount of histologically detectable fibrosis produced by CCl4. This was accompanied by a attenuation of the CCl4 induced increase in alpha2(I) collagen mRNA and a lower (2-fold versus 3-fold) increase in liver hydroxyproline. Furthermore, RA reduced the levels of 3-nitrotyrosine (3-NT) protein adducts and thiobarbituric acid (TBA) reactive substance (TBARS) in the liver, which are formed as results of oxidative stress induced by CCl4 treatment. These in vivo findings support our previous in vitro studies in cultured HSC of the inhibitory effect of RA on type I collagen expression. The data also provide evidence that RA reduces CCl4 induced oxidative stress in liver, suggesting that the anti-fibrotic role of RA is not limited to the inhibition of type I collagen expression.
Wang
Lan
L
Department of Medicine, The Johns Hopkins University School of Medicine, The Johns Hopkins University, Baltimore, MD 21205-2195, USA. lwang6@jhmi.edu
Potter
James J
JJ
Rennie-Tankersley
Lynda
L
Novitskiy
Gennadiy
G
Sipes
Jennifer
J
Mezey
Esteban
E
D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use*
D024042:Collagen Type I; D017392:Thiobarbituric Acid Reactive Substances; D014212:Tretinoin; D006909:Hydroxyproline