PROTECTIVE EFFECT OF SPHINGOSINE 1-PHOSPHATE ON LIVER SINUSOIDAL ENDOTHELIAL CELLS AGAINST ETHANOL-INDUCED APOPTOSIS

• Project/Area Number: 15590689
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: JUNTENDO UNWARILY
• Principal Investigator: KITAMURA Tsuneo JUNTENDO UNIVERSITY, ASSOCIATE PROFESSOR, 医学部, 助教授 (20231285)
• Co-Investigator(Kenkyū-buntansha): ENOMOTO Nobuyuki JUNTENDO UNIVERSITY, INSTRUCTOR, 医学部, 助手 (20348973)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥2,400,000 (Direct Cost: ¥2,400,000); Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: Alcoholic Liver Injury / Liver Sinusoidal Endothelial Cells / Syhingosine 1-Phosphate / Apoptosis / Calcium / Nitric Oxide / eNOS / 細胞内カルシウム

Research Abstract

The mechanism of alcoholic liver disease has been largely investigated in parenchymal hepatocyte. However, little is known about the mechanisms underlying the protection of sinusoidal endothelial cells (SECs) against ethanol-induced injury. Recently, sphingosine 1-phosphate (S1P), a serum-borne bioactive lipid released from activated platelets, has been reported to regulate diverse biological processes, such as cell proliferation, migration, wound healing and inhibition of apoptosis. To test whether S1P may affect biological function of SECs in ethanol-induced liver injury, we examined the effect of extracellular S1P on SECs in primary culture.
Our results show that S1P protects SECs against ethanol-induced injury in primary culture of rat liver, and that the protective effect of S1P may be mediated by activation of Ca^<2+>-sensitive eNOS and subsequent NO formation. This is consistent with previous report that NO generated by eNOS is important for protection of apoptosis in several cell types, and further supported by our present finding that inhibition of calmodulin, a Ca^<2+> binding protein, attenuates S1P-induced eNOS activity in SECs. S1P also ameliorated the decreased DNA synthesis of cells caused by ethanol. We thus propose that S1P, which is possibly released from activated platelets in response to ethanol consumption, could contribute to sinusoidal protection and remodeling in alcoholic liver injury.
Although further research is required to elucidate the molecular interaction between Ca^<2+>, CaM and eNOS activity, our results suggest a possible mechanism for the regulation of ethanol-induced apoptosis in SECs by S1P. Physiological importance of S1P is uncertain. However, our findings may lead to a better understanding of S1P as a target for novel therapeutic strategies in alcoholic liver injury.

Research Products

• [Journal Article] The phosphodiesterase III inhibitor olprinone decreases sensitivit y of rat Kupffer cells to endotoxin. (2004)
  • Author(s): Enomoto N, Takei Y, Hirose M, Ikejima K, Kitamura T, Sato N.
  • Journal Title: Alcohol Clin Exp Res 28
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor. (2004)
  • Author(s): Lang T, Ikejima K, Yoshikawa M, E nomoto N, Iijima K, Kitamura T, Takei Y, Sato N.
  • Journal Title: Biochem Biophys Res Conunun 323 Pages: 1091-5
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Burn injury sensitizes rat Kupffer cells via mechanisms dependent on gut - derived endotoxin. (2004)
  • Author(s): Enomoto N, Takei Y, Yamashina S, Fukuda T, Suzuki S, Ikejima K, Kitamura T, Sato N.
  • Journal Title: J Gastroentefol 39 Pages: 1175-81
  • NAID: 10014091735
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Senescence marker protein-30 regulates Akt activity and contributes to cell survival in Hep G2 cells. (2004)
  • Author(s): Matsuyama S, Kitamura T, Enomoto N, Fujita T, Ishigami A, Handa S, Maruyama N, Zheng D, Ikej ima K, Takei Y, Sato N.
  • Journal Title: Biochem Biophys Res Conunun 321 Pages: 386-390
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The phosphodiesterase III inhibitor olprinone decreases sensitivity of rat Kupffer cells to endotoxin. (2004)
  • Author(s): Enomoto N, Takei Y, Hirose M, Ikejima K, Kitamura T, Sato N.
  • Journal Title: Alcohol Clin Exp Res 28
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor. (2004)
  • Author(s): Lang T, Ikejima K, Yoshikawa M, Enomoto N, Iijima K, Kitamura T, Takei Y, Sato N.
  • Journal Title: Biochem Biophys Res Commun 323 Pages: 1091-1095
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Burn injury sensitizes rat Kupffer cells via mechanisms dependent on gut-derived endotoxin. (2004)
  • Author(s): Enomoto N, Takei Y, Yamashina S, Fukuda T, Suzuki S, Ikejima K, Kitamura T, Sato N.
  • Journal Title: J Gastroentorol 39 Pages: 1175-1181
  • NAID: 10014091735
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Senescence marker protein-30 regulates Akt activity and contributes to cell survival in Hep G2 cells. (2004)
  • Author(s): Matsuyama S, Kitamura T, Enomoto N, Fujita T, Ishigami A, Handa S, Maruyama N, Zheng D, Ikejima K, Takei Y, Sato N.
  • Journal Title: Biochem Biophys Res Commun 321 Pages: 386-390
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Burn injury sensitizes rat Kupffer cells via mechanisms dependent on gut-derived endotoxin. (2004)
  • Author(s): Nobuyuki Enmoto, et al.
  • Journal Title: J Gastroenterol 39 Pages: 1175-1181
• [Journal Article] The phosphodiesterase III inhibitor olprinone decreases sensitivity of rat Kupffer cells to endotoxin (2004)
  • Author(s): Nobuyuki Enmoto, et al.
  • Journal Title: Alcohol Clin Exp Res 28
• [Journal Article] Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor. (2004)
  • Author(s): Lang T, et al.
  • Journal Title: Biochem Biophys Res Commun 323 Pages: 1091-1095
• [Journal Article] Senescence marker protein-30 regulates Akt activity and contributes to cell survival in Hep G2 cells. (2004)
  • Author(s): Shyujirou Matsuyama, et al.
  • Journal Title: Biochem Biophys Res Commun 321 Pages: 386-390
• [Journal Article] Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of PPAR{gamma}, Pioglitazone. (2003)
  • Author(s): Enomoto N, Takei Y, Hirose M, Konno A, Shibuya T, Matsuyama S, Suzuki S, Ikejima K, Kitamura T, Sato N
  • Journal Title: J Pharmacol Exp Ther 306 Pages: 846-854
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of PPAR {gamma}, Pioglitazone. (2003)
  • Author(s): Enomoto N, Takei Y, Hirose M, Konno A, Shibuya T, Matsuyama S, Suzuki S, Ikejima K, Kitamura T, Sato N.
  • Journal Title: Pharmacol Exp Ther 306 Pages: 846-854
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of sphingosine 1-phosphate in protection of liver sinusoidal endothelial cells against ethanol-induced apoptosis.
  • Author(s): Zheng D-M, Kitamura T, Ikejima K, Enomoto N, Yamashina S, Suzuki S, Takei Y, Sato N.
  • Journal Title: Microcirculation Annual 2005 (Asano M, Oda M (eds))(NIHON-IGAKUKAN) 21
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Role of sphingosine 1-phosphate in protection of liver sinusoidal endothelial cells against ethanol-induced apoptosis. Microcirculation Annual 2005 (2005)
  • Author(s): Zheng D-M, Kitamura T, Ikejima K, Enomoto N, Yamashina S, Suzuki S, Takei Y, Sato N.
  • Publisher: Asano M, oda M (eds), 21, NIHON-IGAKUKAN :
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Enomoto N, Takei Y, Hirose M, Konno A, Shibuya T, Matsuyama S, Suzuki S, Ikejima K, Kitamura T, Sato N.: "Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of PPAR {gamma}, Pioglitazone."J Pharmacol Exp Ther. 306. 846-854 (2003)