EFFECT OF CHRONIC IRON OVERLOAD ON PROCOLLAGEN GENE-EXPRESSION

The pathogenesis of hepatic fibrosis and cirrhosis in genetic hemochro matosis may involve a direct effect of excess iron on collagen synthes is in the liver. To investigate this theory, we measured procollagen m essenger RNA levels (types I, III and IV) in the livers of rats in whi ch we produced chronic parenchymal iron overload by feeding them dieta ry carbonyl iron (2.5%, wt/wt) for up to 18 mo. This feeding resulted in predominantly parenchymal iron deposition in a periportal distribut ion similar to that seen in genetic hemochromatosis. Increased amounts of collagen fibrils were observed in iron-loaded livers on electron m icroscopy; all iron-loaded livers showed some periportal fibrosis. Alt hough very high hepatic iron concentrations (range = 340 to 1,100 mumo l/gm dry wt) were achieved in the carbonyl iron-loaded rats, we saw no consistent difference between steady-state messenger RNA levels for p rocollagens types I, III and IV in control and iron-loaded livers exam ined at five different time points up to 18 mo. Messenger RNA levels o f the cytokine transforming growth factor-beta1, which has been implic ated as having a role in the production of extracellular matrix protei ns, were also measured. No significant differences were observed betwe en iron-loaded and control livers. These results suggest that excess p arenchymal iron does not have a direct effect on the expression of the procollagens or transforming growth factor-beta1 genes in iron-loaded livers and that factors other than, or in addition to, iron are neces sary for fibrosis to occur.