385 MOLECULAR STAGES OF PDGFB DRIVEN LIVER FIBROSIS: LESONS FROM A TRANSGENIC MOUSE MODEL

Abstract

underlying pathomechanisms is hampered by the lack of a suitable animal model. To circumvent this problem, we studied hepcidinknockout (KO) mice as a model of iron-overload associated liver disease. Methods: 6 and 12 month-old hepcidin-KO and -wild type (WT) mice fed 3% iron carbonyl-containing diet (Fe-diet) since four weeks of age were compared to age-matched WT and KO animals kept on standard diet. The liver phenotype was quantified serologically as well as morphometrically based on hematoxylin & eosin, Prussian blue and Sirius red stainings. Liver iron content was determined by atomic mass absorption. Liver fibrosis development was determined by collagen RT-PCR and hydroxyproline assay. Results: 6 month Fe-fed hepcidin KO mice (compared to WTs) exhibited (i) increased iron liver contents (2543±114 vs. 1493±136 p < 0.005); (ii) elevated AST and serum iron levels (AST: KO 261±15, WT 142±34 p < 0.05; serum iron: KO 95±3, WT 46±5, p< 0.0005); (iii) increased liver inflammation and hepatocellular apoptosis; (iv) elevated markers of hepatic stellate cell activation (collagen and a-smooth muscle actin mRNA), but no detectable liver fibrosis. 12 month Fe-fed hepcidin KO mice (compared to WTs) also showed increased liver injury markers as well as marked iron accumulation. In addition, they developed liver fibrosis as suggested by collagen RT-PCR, hydroxyproline assay and morphometrical evaluation. As a potential mechanism, hepcidin knockouts fed iron-rich diet exhibited pronounced NFkB activation. Conclusions: Iron-fed hepcidin KOs develop not only a mild chronic liver injury, but also liver fibrosis and therefore represent unique tool to study the mechanism of iron overload-related liver diseases.