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Abstract: The role of osteoactivin (OA) in liver fibrogenesis remains unclear. After feeding wild-type (WT) and OA transgenic (OA-Tg) rats a choline-deficient, l-amino acid-defined (CDAA) diet for 12 weeks, we evaluated liver fibrosis. Hepatic fibrosis and expression of α-smooth muscle actin protein in OA-Tg rats were reduced in comparison to WT rats. Our examination of the expression of 31,100 genes by microarray analysis identified 177 and 256 genes that were upregulated and downregulated, respectively, by at least twofold in OA-Tg rat livers in comparison to WT rat livers. Of these genes, we confirmed a significant downregulation in the expression levels of tissue inhibitor of metalloproteinase-1 and -2, type I collagen, and platelet-derived growth factor receptor-α and -β in the livers of OA-Tg rats. These results indicate that transgenic OA expression attenuates the development of hepatic fibrosis in association with the suppression of specific genes involved in its pathogenesis. [Copyright &y& Elsevier]

Abstract: Administration of a choline-deficient, l-amino acid-defined (CDAA) diet to rats causes steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, a pathology similar to that observed in non-alcoholic steatohepatitis (NASH). The aim of this study was to evaluate if a peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone (PGZ), could ameliorate CDAA diet-induced fatty liver and cirrhosis. Rats were fed a CDAA diet for 1 week and were given the CDAA diet for an additional week with or without PGZ (2-week model). Also, after administration of the CDAA diet for 12 weeks, rats were administered the CDAA diet for an additional 4 weeks with or without PGZ (16-week model). The CDAA diet, administered for either one or 12 weeks, induced fatty liver or cirrhosis with up-regulation of hepatic PPAR-γ expression, respectively. In the 2-week model, rats treated with PGZ for 1 week demonstrated significantly lower hepatic triglyceride content and serum levels of tumor necrosis factor-α. In the 16-week model, treatment for 4 weeks with PGZ ameliorated hepatic fibrosis with a decrease in the expression of procollagen, α-smooth muscle actin, and transforming growth factor-β1 in comparison to rats without PGZ. These results suggest that PPAR-γ agonist is a potential therapeutic modality to treat NASH. [Copyright &y& Elsevier]