Overexpression of the gene for transmembrane 4 superfamily member 4 accelerates liver damage in rats treated with CCl4

Background/Aims: Transmembrane 4 superfamily member 4 (TM4SF4) is up-regulated in regenerating liver after partial hepatectomy in rats, but the in vivo functions of this protein are still largely unknown. Therefore, we investigated the role of TM4SF4 during liver injury. Methods: Expression of TM4SF4 was analyzed by RT-PCR and Western blotting in normal and CCl4-injured rats. Overexpression or reduced expression of TM4SF4 in the liver was achieved by injection of sense or antisense TM4SF4 expression plasmids. Assessment of liver injury (histology, serum ALT and AST levels), apoptosis by TUNEL assay were performed. Expression of injury-related genes was analyzed by quantitative real-time PCR. Results: Overexpression of TM4SF4 in rats after CCl4 treatment showed extensive liver damage and increased levels of serum ALT and AST. Decreased TM4SF4 gene expression showed minimal liver necrosis and depressed ALT and AST levels. Increased expression of TM4SF4 affected the expression levels of growth factors and receptors, such as TNF-alpha, TNFR1 and c-met. Furthermore, pro-apoptotic and anti-apoptotic gene expression was altered after TM4SF4 administration. Conclusions: Rat TM4SF4 is overexpressed in acutely injured liver induced by CCl4 and plays a crucial role in accelerating liver injury, which may be mediated by the TNF-a and HGF/c-met signaling pathways. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.