생명과학회지 (Journal of Life Science)

  • 제21권12호
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  • Pages.1795-1803
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  • 2011
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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지방간 진행 조절에 대한 헤지호그와 에스트로겐의 잠재적 역할

Potential Roles of Hedgehog and Estrogen in Regulating the Progression of Fatty Liver Disease

  • 현정은 (부산대학교 자연과학대학 생명과학과) ;
  • 정영미 (부산대학교 자연과학대학 생명과학과)
  • Hyun, Jeong-Eun (Department of Biological Sciences, College of Natural Science, Pusan National University) ;
  • Jung, Young-Mi (Department of Biological Sciences, College of Natural Science, Pusan National University)
  • 투고 : 2011.09.27
  • 심사 : 2011.11.02
  • 발행 : 2011.12.31
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초록

현대인의 고지방 식습관과 당뇨와 비만인구 증가로 인한 비 알코올성 지방간(nonalcoholic fatty liver)의 유병률(prevalence rate)은 나날이 증가하고 있는 추세이며, 특히 남성과 폐경기 여성에게서 두드러진다. 이런 성 특이적(sex-specific) 간질환의 차이는 여성 호르몬인 에스트로겐(estrogen)의 보호 역할 때문일 것으로 추정되고 있으나, 에스트로겐의 보호 기작을 포함한 지방간의 만성 간질환으로의 진행 메커니즘이 규명되어 있지 않기 때문에 간질환의 효과적인 예방 및 치료책이 없는 실정이다. 그런데 최근에 간 섬유화(fibrosis)를 포함한 만성 간질환의 진행에서 헤지호그(hedgehog) 신호전달계가 주요한 역할을 함이 보고되면서 손상된 간의 회복과 간질환 진행메커니즘 조절을 위한 연구대상으로서 주목 받고 있다. 헤지호그는 발생 및 분화를 조절하는 모포젠(morphogen)으로 성인의 건강한 간에서는 발현되지 않으나, 손상된 간에서 손상 정도에 비례하게 재 발현되며, 섬유화 유발세포인 근섬유아세포(myofibroblasts) 및 간 줄기세포(hepatic progenitor cells)의 활성 및 증식인자로 작용하여 지나친 간 섬유화를 일으킨다. 이에 반해, 에스트로겐은 간 성상세포(hepatic stellate cells)가 근섬유아세포로 활성화되는 것을 억제함으로써 간 섬유화를 막는 것으로 보고되고 있다. 간 섬유화에 대한 헤지호그와 에스트로겐의 상반된 역할 사이의 관련성은 아직 밝혀지지 않고 있으나, 간 섬유화 유발 물질인 오스테오폰틴(osteopontin) 발현에 대한 에스트로겐의 억제효과와 헤지호그에 의한 오스테오폰틴 발현 유도는 오스테오폰틴에 의해 매개되는 에스트로겐과 헤지호그 신호전달계 사이의 연관성을 시사한다. 따라서, 에스트로겐에 의한 헤지호그 신호전달계 조절 메커니즘을 규명하는 것은 간질환 환자에서의 간 섬유화 및 만성 질환으로의 진행을 억제할 수 있는 치료제 개발에 대한 기초 지식을 제공할 수 있다. 이를 위해 간 섬유화에 대한 헤지호그와 에스트로겐의 역할을 확실하게 이해하고, 상호 관련성 및 조절 기작을 밝히는 연구가 선행되어야 할 것이다.

Non-alcoholic fatty liver disease accompanies the rise in the prevalence of obesity, diabetes and the tendency toward high-fat dietary habits. Specifically, the higher prevalence of non-alcoholic fatty liver disease in men and postmenopausal women seems to be caused by the protective effects of estrogen against liver fibrosis, or lack thereof. There are no effective preventive therapies for liver diseases because the mechanisms underlying the progression of fatty liver diseases to chronic liver diseases and the protective effects of estrogen against fibrogenesis remain unclear. Recently, it has been reported that the hedgehog signaling pathway plays an important role in the progression of chronic liver diseases. Hedgehog, a morphogen regulating embryonic liver development, is expressed in injured livers but not in adult healthy livers. The level of hedgehog expression parallels the stages of liver diseases. Hedgehog induces myofibroblast activation and hepatic progenitor cell proliferation and leads to excessive liver fibrosis, whereas estrogen inhibits the activation of hepatic stellate cells to myofibroblasts and prevents liver fibrosis. Although the mechanism underlying the opposing actions of hedgehog and estrogen on liver fibrosis remain unclear, the suppressive effects of estrogen on the expression of osteopontin, a profibrogenic extracellular matrix protein and cytokine, and the inductive effects of hedgehog on osteopontin transcription suggest that estrogen and hedgehog are associated with liver fibrosis regulation. Therefore, further research on the estrogen-mediated regulatory mechanisms underlying the hedgehog-signaling pathway can identify the mechanism underlying liver fibrogenesis and contribute to developing therapies for preventing the progression of fibrosis to chronic liver diseases.

키워드

참고문헌

  1. Alpini, G., J. M. McGill, and N. F. LaRusso. 2002. The pathobiology of biliary epithelia. Hepatology 35, 1256-1268. https://doi.org/10.1053/jhep.2002.33541
  2. Banerjee, A., R. Rose, G. A. Johnson, R. C. Burghardt, and S. K. Ramaiah. 2009. The influence of estrogen on hepatobiliary osteopontin (SPP1) expression in a female rodent model of alcoholic steatohepatitis. Toxicol. Pathol. 37, 492-501. https://doi.org/10.1177/0192623309335633
  3. Beachy, P. A., S. S. Karhadkar, and D. M. Berman. 2004. Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324-331. https://doi.org/10.1038/nature03100
  4. Bebo, B. F., A. Fyfe-Johnson, K. Adlard, A. G. Beam, A. A. Vandenbark, and H. Offner. 2001. Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J. Immunol. 166, 2080-2089. https://doi.org/10.4049/jimmunol.166.3.2080
  5. Borkham-Kamphorst, E., C. R. C. van Roeyen, T. Ostendorf, J. Floege, A. M. Gressner, and R. Weiskirchen. 2007. Pro-fibrogenic potential of PDGF-D in liver fibrosis. J. Hepatol. 46, 1064-1074. https://doi.org/10.1016/j.jhep.2007.01.029
  6. Brussaard, H., J. A. G. Leuven, M. Frolich, C. Kluft, and H. Krans. 1997. Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 40, 843-849. https://doi.org/10.1007/s001250050758
  7. Chitturi, S., V. W. S. Wong, and G. Farrell. 2011. Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground. J. Gastroenterol. Hepatol. 26, 163-172. https://doi.org/10.1111/j.1440-1746.2010.06548.x
  8. Choi, S. S., A. Omenetti, W. K. Syn, and A. M. Diehl. 2010. The role of Hedgehog signaling in fibrogenic liver repair. Int. J. Biochem. Cell B. 43, 238-244. https://doi.org/10.1016/j.biocel.2010.10.015
  9. Das, S., L. G. Harris, B. J. Metge, S. Liu, A. I. Riker, R. S. Samant, and L. A. Shevde. 2009. The hedgehog pathway transcription factor GLI1 promotes malignant behavior of cancer cells by up-regulating osteopontin. J. Biol. Chem. 284, 22888-22897. https://doi.org/10.1074/jbc.M109.021949
  10. Dubal, D. B., H. Zhu, J. Yu, S. W. Rau, P. J. Shughrue, I. Merchenthaler, M. S. Kindy, and P. M. Wise. 2001. Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc. Natl. Acad. Sci. USA 98, 1952-1957. https://doi.org/10.1073/pnas.041483198
  11. Farrell, G. C. and C. Z. Larter. 2006. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43, S99-S112. https://doi.org/10.1002/hep.20973
  12. Fleig, S. V., S. S. Choi, L. Yang, Y. Jung, A. Omenetti, H. M. VanDongen, J. Huang, J. K. Sicklick, and A. M. Diehl. 2007. Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. Lab. Investig. 87, 1227-1239. https://doi.org/10.1038/labinvest.3700689
  13. Hashimoto, E. and K. Tokushige. 2011. Prevalence, gender, ethnic variations, and prognosis of NASH. J. Gastroenterol. 46, 63-69. https://doi.org/10.1007/s00535-010-0311-8
  14. Hirose, Y., T. Itoh, and A. Miyajima. 2009. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Exp. Cell Res. 315, 2648-2657. https://doi.org/10.1016/j.yexcr.2009.06.018
  15. Hodgin, J. B. and N. Maeda. 2002. Minireview: estrogen and mouse models of atherosclerosis. Endocrinology 143, 4495-4501. https://doi.org/10.1210/en.2002-220844
  16. Hooper, J. E. and M. P. Scott. 2005. Communicating with hedgehogs. Nat. Rev. Mol. Cell Biol. 6, 306-317. https://doi.org/10.1038/nrm1622
  17. Ingham, P. W. and A. P. McMahon. 2001. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059-3087. https://doi.org/10.1101/gad.938601
  18. Itagaki, T., I. Shimizu, X. Cheng, Y. Yuan, A. Oshio, K. Tamaki, H. Fukuno, H. Honda, Y. Okamura, and S. Ito. 2005. Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells. Gut 54, 1782-1789. https://doi.org/10.1136/gut.2004.053728
  19. Jansson, L., T. Olsson, and R. Holmdahl. 1994. Estrogen induces a potent suppression of experimental autoimmune encephalomyelities and collagen-induced arthritis in mice. J. Neuroimmunol. 53, 203-207. https://doi.org/10.1016/0165-5728(94)90030-2
  20. Jung, Y., K. D. Brown, R. P. Witek, A. Omenetti, L. Yang, M. Vandongen, R. J. Milton, I. N. Hines, R. A. Rippe, and L. Spahr. 2008. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 134, 1532-1543. https://doi.org/10.1053/j.gastro.2008.02.022
  21. Jung, Y., W. K. Syn., A. Omenetti A, M. Abdelmalek, C. D. Guy, L. Yang, J. Wang, R. P. Witek, C. M. Fearing, T. A. Pereira, V. Teaberry, S. S. Choi, J. Conde-Vancells, G. F. Karaca, and A. M. Diehl. 2009. Hedgehog-mediated epithelial to mesenchymal transition promotes fibrogenesis in mice and humans with non-alcoholic fatty liver disease. Gastroenterology 137, 1478-1488. https://doi.org/10.1053/j.gastro.2009.06.051
  22. Jung, Y., S. J. McCall, Y. X. Li, and A. M. Diehl. 2007. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology 45, 1091-1096. https://doi.org/10.1002/hep.21660
  23. Kameda, C., M. Nakamura, H. Tanaka, A. Yamasaki, M. Kubo, M. Tanaka, H. Onishi, and M. Katano. 2010. Oestrogen receptor-α contributes to the regulation of the hedgehog signalling pathway in $ER\alpha$-positive gastric cancer. Br. J. Cancer 102, 738-747. https://doi.org/10.1038/sj.bjc.6605517
  24. Katayama, S., K. Ashizawa, H. Gohma, T. Fukuhara, K. Narumi, Y. Tsuzuki, H. Tatemoto, T. Nakada, and K. Nagai. 2006. The expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats. Toxicol. Appl. Pharmacol. 217, 375-383. https://doi.org/10.1016/j.taap.2006.10.003
  25. Koga, K., M. Nakamura, H. Nakashima, T. Akiyoshi, M. Kubo, N. Sato, S. Kuroki, M. Nomura, M. Tanaka, and M. Katano. 2008. Novel link between estrogen receptor α and hedgehog pathway in breast cancer. Anticancer Res. 28, 731-739.
  26. Lee, J. J., D. P. von Kessler, S. Parks, and P. A. Beachy. 1992. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell 71, 33-50. https://doi.org/10.1016/0092-8674(92)90264-D
  27. Martino, V. D., P. Lebray, R. P. Myers, E. Pannier, V. Paradis, F. Charlotte, J. Moussalli, D. Thabut, C. Buffet, and T. Poynard. 2004. Progression of liver fibrosis in women infected with hepatitis C: Long term benefit of estrogen exposure. Hepatology 40, 1426-1433. https://doi.org/10.1002/hep.20463
  28. Matsuda, J., M. T. Vanier, Y. Saito, and K. Suzuki. 2001. Dramatic phenotypic improvement during pregnancy in a genetic leukodystrophy: estrogen appears to be a critical factor. Hum. Mol. Genet. 10, 2709-2715. https://doi.org/10.1093/hmg/10.23.2709
  29. Meindl Beinker, N. M. and S. Dooley. 2008. Transforming growth factor $\alpha$ and hepatocyte transdifferentiation in liver fibrogenesis. J. Gastroenterol. Hepatol. 23, S122-S127. https://doi.org/10.1111/j.1440-1746.2007.05297.x
  30. Miyamoto, N., M. Mandai, I. Suzuma, K. Suzuma, K. Kobayashi, and Y. Honda. 1999. Estrogen protects against cellular infiltration by reducing the expressions of E-selectin and IL-6 in endotoxin-induced uveitis. J. Immunol. 163, 374-379.
  31. Ochoa, B., W. K. Syn, I. Delgado, G. F. Karaca, Y. Jung, J. Wang, A. M. Zubiaga, O. Fresnedo, A. Omenetti, and M. Zdanowicz. 2010. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology 51, 1712-1723. https://doi.org/10.1002/hep.23525
  32. Omenetti, A., S. Choi, G. Michelotti, and A. M. Diehl. 2010. Hedgehog signaling in the liver. J. Hepatol. 54, 366-373. https://doi.org/10.1016/j.jhep.2010.10.003
  33. Omenetti, A. and A. M. Diehl. 2008. The adventures of sonic hedgehog in development and repair. II. Sonic hedgehog and liver development, inflammation, and cancer. Am. J. Physiol-Gastr. L. 294, G595-G598.
  34. Omenetti, A., Y. Popov, Y. Jung, S. S. Choi, R. P. Witek, L. Yang, K. D. Brown, D. Schuppan, and A. M. Diehl. 2008. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 57, 1275-1282. https://doi.org/10.1136/gut.2008.148619
  35. Omenetti, A., A. Porrello, Y. Jung, L. Yang, Y. Popov, S. S. Choi, R. P. Witek, G. Alpini, J. Venter, and H. M. Vandongen. 2008. Hedgehog signaling regulates epithelial- mesenchymal transition during biliary fibrosis in rodents and humans. J. Clin. Invest. 118, 3331-3342.
  36. Omenetti, A., W. K. Syn, Y. Jung, H. Francis, A. Porrello, R. P. Witek, S. S. Choi, L. Yang, M. J. Mayo, and M. E. Gershwin. 2009. Repair related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology 50, 518-527. https://doi.org/10.1002/hep.23019
  37. Omenetti, A., L. Yang, Y. X. Li, S. J. McCall, Y. Jung, J. K. Sicklick, J. Huang, S. Choi, A. Suzuki, and A. M. Diehl. 2007. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab. Investig. 87, 499-514.
  38. Pan, Y., C. B. Bai, A. L. Joyner, and B. Wang. 2006. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell Biol. 26, 3365-3377. https://doi.org/10.1128/MCB.26.9.3365-3377.2006
  39. Pan, Y., C. Wang, and B. Wang. 2009. Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev. Biol. 326, 177-189. https://doi.org/10.1016/j.ydbio.2008.11.009
  40. Riobo, N. A., K. Lu, X. Ai, G. M. Haines and C. P. Emerson. 2006. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc. Natl. Acad. Sci. USA 103, 4505-4510. https://doi.org/10.1073/pnas.0504337103
  41. Rosette, C. and M. Karin. 1995. Cytoskeletal control of gene expression: depolymerization of microtubules activates NF-kappa B. J. Cell Biol. 128, 1111-1119. https://doi.org/10.1083/jcb.128.6.1111
  42. Schuske, K., J. E. Hooper, and M. P. Scott. 1994. patched overexpression causes loss of wingless expression in Drosophila embryos. Dev. Biol. 164, 300-311. https://doi.org/10.1006/dbio.1994.1200
  43. Shao, D. D., R. Suresh, V. Vakil, R. H. Gomer, and D. Pilling. 2008. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J. Leukoc. Biol. 83, 1323-1333. https://doi.org/10.1189/jlb.1107782
  44. Shimizu, I. and S. Ito. 2007. Protection of estrogens against the progression of chronic liver disease. Hepatol. Res. 37, 239-247. https://doi.org/10.1111/j.1872-034X.2007.00032.x
  45. Sicklick, J. K., Y. X. Li, S. S. Choi, Y. Qi, W. Chen, M. Bustamante, J. Huang, M. Zdanowicz, T. Camp, and M. S. Torbenson. 2005. Role for hedgehog signaling in hepatic stellate cell activation and viability. Lab. Invest. 85, 1368-1380. https://doi.org/10.1038/labinvest.3700349
  46. Sicklick, J. K., Y. X. Li, A. Melhem, E. Schmelzer, M. Zdanowicz, J. Huang, M. Caballero, J. H. Fair, J. W. Ludlow, and R. E. McClelland. 2006. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am. J. Physiol-Gastr. L. 290, G859-G870.
  47. Suzuki, A. and M. F. Abdelmalek. 2009. Nonalcoholic fatty liver disease in women. Womens Health (Lond Engl). 5, 191-203. https://doi.org/10.2217/17455057.5.2.191
  48. Syn, W. K., S. S. Choi, E. Liaskou, G. F. Karaca, K. M. Agboola, Y. H. Oo, Z. Mi, T. A. Pereira, M. Zdanowicz, and P. Malladi. 2011. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53, 106-115. https://doi.org/10.1002/hep.23998
  49. Syn, W. K., Y. Htun Oo, T. A. Pereira, G. F. Karaca, Y. Jung, A. Omenetti, R. P. Witek, S. S. Choi, C. D. Guy, and C. M. Fearing. 2010. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998-2007. https://doi.org/10.1002/hep.23599
  50. Tau, K., T. Hefferan, K. Waters, J. Robinson, M. Subramaniam, B. Riggs, and T. Spelsberg. 1998. Estrogen regulation of a transforming growth factor-{beta} inducible early gene that inhibits deoxyribonucleic acid synthesis in human osteoblasts. Endocrinology 139, 1346-1353. https://doi.org/10.1210/en.139.3.1346
  51. Thiery, J. P. 2003. Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15, 740-746. https://doi.org/10.1016/j.ceb.2003.10.006
  52. Van den Brink, G. R. 2007. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol. Rev. 87, 1343-1375. https://doi.org/10.1152/physrev.00054.2006
  53. Varjosalo, M., S. P. Li, and J. Taipale. 2006. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev. Cell 10, 177-186. https://doi.org/10.1016/j.devcel.2005.12.014
  54. Varjosalo, M. and J. Taipale. 2008. Hedgehog: functions and mechanisms. Genes Dev. 22, 2454-2472. https://doi.org/10.1101/gad.1693608
  55. Villanueva, A., P. Newell, D. Y. Chiang, S. L. Friedman, and J. M. Llovet. 2007. Genomics and signaling pathways in hepatocellular carcinoma. Semin. Liver Dis. 27, 55-76. https://doi.org/10.1055/s-2006-960171
  56. Witek, R. P., W. C. Stone, F. G. Karaca, W. K. Syn, T. A. Pereira, K. M. Agboola, A. Omenetti, Y. Jung, V. Teaberry, and S. S. Choi. 2009. Pan caspase inhibitor VX 166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50, 1421-1430. https://doi.org/10.1002/hep.23167
  57. Yang, L., Y. Wang, H. Mao, S. Fleig, A. Omenetti, K. D. Brown, J. K. Sicklick, Y. X. Li, and A. M. Diehl. 2008. Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J. Hepatol. 48, 98-106. https://doi.org/10.1016/j.jhep.2007.07.032
  58. Zeisberg, M., J. Hanai, H. Sugimoto, T. Mammoto, D. Charytan, F. Strutz, and R. Kalluri. 2003. BMP-7 counteracts TGF-$\alpha1$-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964-968. https://doi.org/10.1038/nm888

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