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Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARγ agonist KR62776

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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.

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References

  • Ahn, J. H., Shin, M. S., Jung, S. H., Kang, S. K., Kim, K. R., Rhee, S. D., Jung, W. H., Yang, S. D., Kim, S. J., Woo, J. R., Lee, J. H., Cheon, H. G., and Kim, S. S., Indene derivatives: A novel template for peroxosome proliferatoractivated receptor γ (PPARγ) agonists. J. Med. Chem., 49, 4781–4784 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Bae, M. A., Pie, J. E., and Song, B. J., Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH2-terminal protein kinase-related cell death pathway. Mol. Pharmacol., 60, 847–856 (2001).

    CAS  PubMed  Google Scholar 

  • Bae, M. A. and Song, B. J., Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells. Mol. Pharmacol., 63, 401–408 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Baroni, G. S., D’Ambrosio, L., Curto, P., Casini, A., Mancini, R., Jezequel, A. M., and Benedetti, A., Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. Hepatology, 23, 1189–1199 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Berger, J. and Moller, D. E., The mechanisms of action of PPARs. Annu. Rev. Med., 53, 409–435 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Blazejewski, S., Preaux, A. M., Mallat, A., Brocherion, I., Mavier, P., Dhumeaux, D., Hartmann, D., Schuppan, D., and Rosenbaum, J., Human myofibroblast-like cells obtained by outgrowth are representative of the fibrogenic cells in the liver. Hepatology, 22, 788–797 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Bruck, R., Genina, O., Aeed, H., Alexiev, R., Nagler, A., Avni, Y., and Pines, M., Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Hepatology, 33, 379–386 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Date, M., Fukuchi, K., Morita, S., Takahashi, H., and Ohura, K., 15-Deoxy-delta12,14-prostaglandin J2, a ligand for peroxisome proliferators-activated receptor-gamma, induces apoptosis in human hepatoma cells. Liver Int., 23, 460–466 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Dubuquoy, L., Dharancy, S., Nutten, S., Petterson, S., Auwerx, J., and Desreumaux, P., Role of peroxisome proliferatoractivated receptor and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet, 360, 1410–1418 (2000).

    Article  Google Scholar 

  • Enomoto, N., Takei, Y., Hirose, M., Konno, A., Shibuya, T., Matsuyama, S., Suzuki, S., Kitamura, K. I., and Sato, N., Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptorgamma, pioglitazone. J. Pharmacol. Exp. Ther., 306, 846–854 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Friedman, S. L., Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem., 275, 2247–2250 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Galli, A., Crabb, D. W., Ceni, E., Salzano, R., Mello, T., Svegliati-Baroni, G., Ridolfi, F., Trozzi, L., Surrenti, C., and Casini, A., Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology,122, 1924–1940 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Garcia, L., Hernandez, I., Sandoval, A., Salazar, A., Garcia, J., Vera, J., Grijalva, G., Muriel, P., Margolin, S., and Armendariz-Borunda, J., Pirfenidone effectively reverses experimental liver fibrosis. J. Hepatol., 37, 797–805 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Geerts, A., Lazou, J. M., De Bleser, P., and Wisse, E., Tissue distribution, quantitation and proliferation kinetics of fatstoring cells in carbon tetrachloride-injured rat liver. Hepatology, 13, 1193–1202 (1991)

    CAS  PubMed  Google Scholar 

  • Kawaguchi, K., Sakaida, I., Tsuchiya, M., Omori, K., Takami, T., and Okita, K., Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem. Biophys. Res. Commun., 315, 187–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Kon, K., Ikejima, K., Hirose, M., Yoshikawa, M., Enomoto, N., Kitamura, T., Takei, Y., and Sato, N., Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem. Biophys. Res. Commun., 291, 55–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Li, L., Tao, J., Davaille, J., Feral, C., Mallat, A., Rieusset, J., Vidal, H., and Lotersztajn, S., 15-Deoxy-Δ12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. J. Biol. Chem., 276, 38152–38158 (2001).

    CAS  PubMed  Google Scholar 

  • Marra, F., Efsen, E., Romanelli, R. G., Caligiuri, A., Pastacaldi, S., Batignani, G., Bonacchi, A., Caporale, R., Laffi, G., Pinzani, M., and Gentilini, P., Ligands of peroxisome proliferator-activated receptor g modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology, 119, 466–478 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Milani, S., Herbst, H., Schuppan, D., Kim, K. Y., Riecken, E. O., and Stein, H., Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology, 98, 175–184 (1990).

    CAS  PubMed  Google Scholar 

  • Miyahara, T., Schrum, L., Rippe, R., Xiong, S., Yee, H. F. Jr, Motomura, K., Anania, F. A., Willson, T. M., and Tsukamoto, H., Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J. Biol. Chem., 275, 35715–35722 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Morgan, D. O., Principles of CDK regulation. Nature, 374, 131–134 (1996).

    Article  Google Scholar 

  • Ohata, M., Suzuki, H., Sakamoto, K., Hashimoto, K., Nakajima, H., Yamauchi, M., Hokkyo, K., Yamada, H., and Toda, G., Pioglitazone prevents acute liver injury induced by ethanol and lipopolysaccharide through the suppression of tumor necrosis factor-a. Alcohol. Clin. Exp. Res., 28, 139S–144S (2004).

    CAS  PubMed  Google Scholar 

  • Pines, M., Knopov, V., Genina, O., Lavelin, I., and Nagler, A., Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis. J. Hepatol., 27, 391–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Promrat, K., Lutchman, G., Uwaifo, G. I., Freedman, R. J., Soza, A., Heller, T., Doo, E., Ghany, M., Premkumar, A., Park, Y., Liang, T. J., Yanovski, J. A., Kleiner, D. E., and Hoofnagle, J. H., A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology, 39, 188–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Rangwala, S. M. and Lazar, M. A., Peroxisome proliferatoractivated receptor gamma in diabetes and metabolism. Trends Pharmacol. Sci., 25, 331–336 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Reeves, H. L. and Friedman, S. L., Activation of hepatic stellate cells-a key issue in liver fibrosis. Front Biosci., 7, 808–826 (2002).

    Article  Google Scholar 

  • Sakaida, I., Matsumura, Y., Kubota, M., Kayano, K., Takenaka, K., and Okita, K., 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. Hepatology, 23, 755–763 (1996).

    CAS  PubMed  Google Scholar 

  • Sato, O., Kuriki, C., Fukui, Y., and Motojima, K., 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. J. Biol. Chem., 277, 15703–15711 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Sherr, C. J. and Roberts, J. M., CDK inhibitors: positive and negative regulators of G1 phase progression. Genes Dev., 13, 1501–1512 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Tada, S., Nakamuta, M., Enjoji, M., Sugimoto, R., Iwamoto, H., Kato, M., Nakashima, Y., and Nawata, H., Pirfenidone inhibits dimethylnitrosamine-induced hepatic fibrosis in rats. Clin Exp. Pharmacol. Physiol., 28, 522–527 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Vogel, S., Piantedosi, R., Frank, J., Lalazar, A., Rockey, D. C., Friedman, S. L., and Blaner, W. S., An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro. J. Lipid Res., 41, 882–893 (2000).

    CAS  PubMed  Google Scholar 

  • Wang, C., Fu, M., D’Amico, M., Albanese, C., Zhou, J. N., Brownlee, M., Lisanti, M. P., Chatterjee, V. K., Lazar, M. A., and Pestell, R. G., Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1. Mol. Cell. Biol., 21, 3057–3070 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Wu, J. and Norton, P. A., Animal models of liver fibrosis. Scand. J. Gastroenterol., 31, 1137–1143 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Xu, J., Fu, Y., and Chen, A., Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am. J. Physiol. Gastrointest. Liver Physiol., 285, 20–30 (2003).

    Google Scholar 

  • Zhao, W. X., Zhao, J., Liang, C. L., Zhao, B., Pang, R. Q., and Pan, X. H., Effect of caffeic acid phenethyl ester on proliferation and apoptosis of hepatic stellate cells in vitro. World J. Gastroenterol., 9, 1278–1281 (2003).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Drug Discovery Platform Technology Team, Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejon, 305-600, Korea

    Myung-Ae Bae

  2. Center for Metabolic Syndrome Therapeutics, Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejon, 305-600, Korea

    Sang Dal Rhee, Won Hoon Jung, Jin Hee Ahn & Hyae Gyeong Cheon

  3. Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892-9410, USA

    Byoung-Joon Song

  4. Center for Metabolic Syndrome Therapeutics, Korea Research Institute of Chemical Technology, Daejon, 305-600, Korea

    Hyae Gyeong Cheon

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  1. Myung-Ae Bae
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  2. Sang Dal Rhee
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  3. Won Hoon Jung
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  4. Jin Hee Ahn
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  5. Byoung-Joon Song
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  6. Hyae Gyeong Cheon
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Correspondence to Myung-Ae Bae or Hyae Gyeong Cheon.

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Bae, MA., Dal Rhee, S., Jung, W.H. et al. Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARγ agonist KR62776. Arch. Pharm. Res. 33, 433–442 (2010). https://doi.org/10.1007/s12272-010-0313-3

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  • DOI: https://doi.org/10.1007/s12272-010-0313-3

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