High, but not low, dietary retinoids aggravate manifestation of rat liver fibrosis.
BACKGROUND
Although there is strong implication that retinoids regulate Ito cell proliferation and collagen synthesis, results from in vivo studies on the relationship between vitamin A and liver fibrosis are conflicting. The present study focuses on the role of vitamin A in carbon tetrachloride (CCl4)-induced fibrosis by chronic feeding of rats with either a vitamin A-supplemented or -depleted diet.


RESULTS
In animals with high dietary hepatic retinoid levels, liver fibrosis was more pronounced and was associated with an increased CCl4-toxicity resulting in high mortality (73%). Enhanced liver fibrosis was confirmed by in vivo fluorescence microscopic determination of both collagen deposits (7.4 +/- 1.1 vs 3.9 +/- 0.3% in high vitamin A diet-fed and standard diet-fed fibrotic animals, respectively; P < 0.05) and rarefication of sinusoids (1.5 +/- 0.2 vs 2.4 +/- 0.2 sinusoids/200 microm in high vitamin A diet-fed and standard diet-fed fibrotic animals, respectively; P < 0.05). It was further associated with decreased bile flow and increased parenchymal cell damage. CCl4 reduced hepatic retinoid levels in high vitamin A diet-fed animals, but restored hepatic retinoid levels in animals fed with a vitamin A-deficient diet, implying major interference of vitamin A metabolism with hepatotoxic agents such as CCl4. Low vitamin A feeding did not modulate liver fibrogenesis and caused no mortality.


CONCLUSIONS
These results show that the vitamin A status of the liver plays an important role in liver fibrogenesis. While dietary vitamin A shortage does not promote liver fibrogenesis, high levels of vitamin A have the potential to increase systemic and hepatic toxicity of CCl4. Thus, the narrow therapeutic window for nutritional vitamin A substitution must take into account that liver fibrotic patients may display enhanced susceptibility to the adverse effects of vitamin A.
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany. exbvol@uniklinik-saarland.de
Brigitte
B
Vollmar
Christine
C
Heckmann
Sven
S
Richter
Michael D
MD
Menger
D000818:Animals; D001646:Bile / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000378:metabolism; D004032:Diet; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008856:Microscopy, Fluorescence; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D014801:Vitamin A / Q000008:administration & dosage / Q000502:physiology*
D014801:Vitamin A; D003094:Collagen; D002251:Carbon Tetrachloride