Retinyl palmitate reduces hepatic fibrosis in rats induced by dimethylnitrosamine or pig serum.
OBJECTIVE
Lipid peroxidation has been found to be associated with Ito cell activation. Ito cells are the principal collagen-producing cells and the main storage sites of retinoids. However, the relationship between retinoids and hepatic fibrosis is complex. The aim of this study was to elucidate the role of retinoids as a fibrosuppressant: the effects of retinoids on hepatic fibrosis induced in rats by dimethylnitrosamine or pig serum, as well as on rat Ito cells in primary culture, were examined in order to assess the antioxidant activity of retinoids.


METHODS
Male Wistar rats were given a single injection of 40 mg/kg dimethylnitrosamine or 0.5 ml PS twice weekly for 10 weeks. In each model, rats were treated with retinyl palmitate for 2 weeks before hepatotoxin treatments or for the last 2 weeks of the treatments. The cumulative amount of retinyl palmitate administered in each experiment was 2, 10, or 20x10(4) IU/rat.


RESULTS
Retinyl palmitate treatment before or after administration of dimethylnitrosamine or pig serum suppressed the induction of hepatic fibrosis, restored hepatic retinyl palmitate levels, prevented increases in hepatic levels of collagen and malondialdehyde, a product of lipid peroxidation, and prevented increases in deposition of type III collagen and the number of alpha-smooth muscle actin (alpha-SMA) positive-Ito cells in the liver. Retinyl palmitate supplementation resulted in a dose-dependent reduction of alpha-SMA expression and an oxidative burst in cultured Ito cells. In addition, retinyl palmitate inhibited Fe2+/adenosine 5'-diphosphate-induced lipid peroxidation in rat liver mitochondria and showed radical scavenging activity.


CONCLUSIONS
These findings suggest that retinyl palmitate may suppress the induction of hepatic fibrosis, at least in part, by the inhibition of Ito cell activation through its antioxidant activity.
Mizobuchi
Y
Y
Second Department of Internal Medicine, School of Medicine, University of Tokushima, Japan.
Shimizu
I
I
Yasuda
M
M
Hori
H
H
Shono
M
M
Ito
S
S
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001790:Blood Physiological Phenomena; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000084562:Retinyl Esters; D013552:Swine; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000975:Antioxidants; D004224:Diterpenes; D000084562:Retinyl Esters; D014801:Vitamin A; C014794:retinol palmitate; D004128:Dimethylnitrosamine