A novel synthetic oleanolic acid derivative (CPU-II2) attenuates liver fibrosis in mice through regulating the function of hepatic stellate cells.
Regulation on the function of the hepatic stellate cells (HSCs) is one of the proposed therapeutic approaches to liver fibrosis. In the present study, we examined the in vitro and in vivo effects of CPU-II2, a novel synthetic oleanolic acid (OLA) derivative with nitrate, on hepatic fibrosis. This compound alleviated CCl4-induced hepatic fibrosis in mice with a decrease in hepatic hydroxyproline (Hyp) content and histological changes. CPU-II2 also attenuated the mRNA expression of alpha-smooth muscle actin (alpha-SMA) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) induced by CCl4 in mice and reduced both mRNA and protein levels of alpha-SMA in HSC-T6 cells. Interestingly, CPU-II2 did not affect the survival of HSC-T6 cells but decreased the expression of procollagen-alpha1 (I) in HSC-T6 cells through down-regulating the phosphorylation of p38 MAPK.


CONCLUSIONS
CPU-II2 attenuates the development of liver fibrosis rather by regulating the function of HSCs through p38 MAPK pathway than by damaging the stellate cells.
Wu
Li-Mei
LM
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing, 210093, China.
Wu
Xing-Xin
XX
Sun
Yang
Y
Kong
Xiang-Wen
XW
Zhang
Yi-Hua
YH
Xu
Qiang
Q
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D015536:Down-Regulation / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000199:Actins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D019715:Tissue Inhibitor of Metalloproteinase-1; D009828:Oleanolic Acid; D002251:Carbon Tetrachloride; D048051:p38 Mitogen-Activated Protein Kinases; D006909:Hydroxyproline