Preservation of basal AcSDKP attenuates carbon tetrachloride-induced fibrosis in the rat liver.
OBJECTIVE
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous tetrapeptide which has antifibrogenic effects at physiological concentrations in various tissues. AcSDKP is produced locally in the liver, however, little is known about its biological effect in this organ. We hypothesize that basal levels of endogenous AcSDKP decrease during the development of liver fibrosis and preservation of basal AcSDKP attenuates liver fibrosis.


METHODS
Endogenous levels of AcSDKP in the liver were measured by enzyme immunoassay after 2, 6, and 10 weeks of carbon tetrachloride (CCl(4))-induced liver fibrosis in rats. Subcutaneous osmotic pump infusion of vehicle or AcSDKP (800 microg/kg/day) was administered to CCl(4)-treated rats for 8 weeks to study the effect of exogenous AcSDKP on liver fibrosis. The effect of AcSDKP on profibrogenic properties of hepatic stellate cells was studied in vitro.


RESULTS
Endogenous AcSDKP was significantly decreased in the liver of CCl(4)-treated rats. Chronic AcSDKP infusion preserved basal levels of AcSDKP and reduced liver injury, inflammation, fibrosis, and profibrogenic transforming growth factor-beta signaling. This was demonstrated by decreased aminotransferase serum levels, CD45 positive cells, collagen accumulation, alpha-smooth muscle actin positivity, transforming growth factor-beta1, phosphorylated Smad2/3 protein, increased bone morphogenetic protein-7, and phosphorylated Smad1/5/8. Further, AcSDKP exerts antifibrogenic effects on hepatic stellate cells (HSCs) by downregulation of HSC activation in vitro.


CONCLUSIONS
Maintaining physiological levels of AcSDKP is critical in negatively regulating the development of fibrosis in chronic liver injury. Preservation of AcSDKP may be a useful therapeutic approach in the management of liver fibrosis.
Chen
Yuan-Wen
YW
Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Liu
Bo-Wei
BW
Zhang
Yu-Jian
YJ
Chen
Ying-Wei
YW
Dong
Guo-Fang
GF
Ding
Xiao-Dong
XD
Xu
Lei-Ming
LM
Pat
Betty
B
Fan
Jiang-Gao
JG
Li
Ding-Guo
DG
D000199:Actins / Q000378:metabolism; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000199:Actins; D003094:Collagen; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat; C058504:goralatide