Overexpression of the gene for transmembrane 4 superfamily member 4 accelerates liver damage in rats treated with CCl4.
OBJECTIVE
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-alpha and HGF/c-met signaling pathways.
Qiu
Jie
J
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, People's Republic of China.
Liu
Zhanwu
Z
Da
Liang
L
Li
Ying
Y
Xuan
Haixing
H
Lin
Qishui
Q
Li
Feng
F
Wang
Yifei
Y
Li
Zaiping
Z
Zhao
Mujun
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology*; D016373:DNA, Antisense / Q000235:genetics; D015870:Gene Expression; D022781:Hepatocytes / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics*; D009336:Necrosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016373:DNA, Antisense; D008562:Membrane Glycoproteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C486078:Tm4sf4 protein, rat; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019859:Proto-Oncogene Proteins c-met