Selective Inhibition of Activated Stellate Cells and Protection from Carbon Tetrachloride-Induced Liver Injury in Rats by a New PPARγ agonist KR62776

다국어 초록 (Multilingual Abstract)

Activated hepatic stellate cells (HSC) are the primary source of extracellular matrix proteins found in liver fibrosis/cirrhosis patients. Therefore, the prevention of HSC activation is an important strategy for treating severe liver injury. This study examined the effects of KR62776, a new peroxisome proliferator-activated receptor γ (PPARγ) agonist, on the rate of cell proliferation and expression of α-smooth muscle actin (α-SMA) in rat hepatic stellate HSC-T6 cells. In addition, its effects on the liver damage induced by carbon tetrachloride were investigated. KR62776 caused the apoptosis of activated HSC-T6 cells with the concomitant decrease in the α-smooth muscle actin levels in a time- and concentration-dependent manner.
However, KR62776 did not cause the apoptosis of human HepG2 and rat McARH7777 hepatoma cells, suggesting that KR62776 has a specific effect on stellate cells. KR62776 increased the levels of Gadd45, p27, p21 and PPARγ proteins but decreased the cell cyclerelated proteins, such as cdk2, cyclin B and cyclin D1. These changes were reversed by BADGE, a specific PPARγ antagonist, indicating that the effects of KR62776 are, at least in part, PPARγ-dependent. In addition, KR62776 administration showed some protection against carbon tetrachloride-induced hepatocellular damage in rats. Overall, these results suggest that KR62776 may have potential in the chemoprevention of liver fibrosis/cirrhosis.

참고문헌 (Reference)

1 Geerts, A, "Tissue distribution, quantitation and proliferation kinetics of fatstoring cells in carbon tetrachloride-injured rat liver" 13 : 1193-1202, 1991

2 Sakaida, I, "The prolyl 4-hydroxylase inhibitor HOE-077 prevents activation of Ito Cells, reducing procollagen gene expression in rat liver fibrosis induced by cholinedeficient L-amino acid-defined diet" 23 : 755-763, 1996

3 Berger, J, "The mechanisms of action of PPARs" 53 : 409-435, 2002

4 Dubuquoy, L, "Role of peroxisome proliferatoractivated receptor and retinoid X receptor heterodimer in hepatogastroenterological diseases" 360 : 1410-1418, 2000

5 Milani, S, "Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis" 98 : 175-184, 1990

6 Morgan, D. O, "Principles of CDK regulation" 374 : 131-134, 1996

7 Enomoto, N, "Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptorgamma,pioglitazone" 306 : 846-854, 2003

8 Tada, S, "Pirfenidone inhibits dimethylnitrosamine-induced hepatic fibrosis in rats" 28 : 522-527, 2001

9 Garcia, L, "Pirfenidone effectively reverses experimental liver fibrosis" 37 : 797-805, 2002

10 Kawaguchi, K, "Pioglitazone prevents hepatic steatosis,fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet" 315 : 187-195, 2004

11 Kon, K, "Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride" 291 : 55-61, 2002

12 Ohata, M, "Pioglitazone prevents acute liver injury induced by ethanol and lipopolysaccharide through the suppression of tumor necrosis factor-a. Alcohol" 28 : 139S-144S, 2004

13 Rangwala, S. M, "Peroxisome proliferatoractivated receptor gamma in diabetes and metabolism" 25 : 331-336, 2004

14 Miyahara, T, "Peroxisome proliferator-activated receptors and hepatic stellate cell activation" 275 : 35715-35722, 2000

15 Friedman, S. L, "Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury" 275 : 2247-2250, 2000

16 Marra, F, "Ligands of peroxisome proliferator-activated receptor g modulate profibrogenic and proinflammatory actions in hepatic stellate cells" 119 : 466-478, 2000

17 Baroni, G. S, "Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis" 23 : 1189-1199, 1996

18 Wang, C, "Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1" 21 : 3057-3070, 2001

19 Ahn, J. H, "Indene derivatives: A novel template for peroxosome proliferatoractivated receptor γ (PPARγ) agonists" 49 : 4781-4784, 2006

20 Blazejewski, S, "Human myofibroblast-like cells obtained by outgrowth are representative of the fibrogenic cells in the liver" 22 : 788-797, 1995

21 Pines, M, "Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis" 27 : 391-398, 1997

22 Bruck, R, "Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats" 33 : 379-386, 2001

23 Zhao, W. X, "Effect of caffeic acid phenethyl ester on proliferation and apoptosis of hepatic stellate cells in vitro" 9 : 1278-1281, 2003

24 Sato, O, "Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands" 277 : 15703-15711, 2002

25 Bae, M. A, "Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells" 63 : 401-408, 2003

26 Sherr, C. J, "CDK inhibitors: positive and negative regulators of G1 phase progression" 13 : 1501-1512, 1999

27 Galli, A, "Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro" 122 : 1924-1940, 2002

28 Wu, J, "Animal models of liver fibrosis" 31 : 1137-1143, 1996

29 Vogel, S, "An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro" 41 : 882-893, 2000

30 Xu, J, "Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth" 285 : 20-30, 2003

31 Reeves, H. L, "Activation of hepatic stellate cells-a key issue in liver fibrosis" 7 : 808-826, 2002

32 Bae, M. A, "Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH2-terminal protein kinase-related cell death pathway" 60 : 847-856, 2001

33 Promrat, K, "A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis" 39 : 188-196, 2004

34 Li, L, "15-Deoxy-Δ12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts.A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors" 276 : 38152-38158, 2001

35 Date, M, "15-Deoxy-delta12,14-prostaglandin J2, a ligand for peroxisome proliferators-activated receptor-gamma, induces apoptosis in human hepatoma cells" 23 : 460-466, 2003