Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5

Hitoshi Ikeda, Hiroaki Satoh, Mikio Yanase, Yukiko Inoue, Tomoaki Tomiya, Masahiro Arai, Kazuaki Tejima, Kayo Nagashima, Hisato Maekawa, Naohisa Yahagi, Yutaka Yatomi, Soutaro Sakurada, Yoh Takuwa, Itsuro Ogata, Satoshi Kimura, Kenji Fujiwara

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Sphingosine 1-phosphate (SIP), a ligand for G protein-coupled endothelial differentiation gene-1 (Edg-1), Edg-3, Edg-5, Edg-6, and Edg-8, elicits a variety of responses by cells. Prominent among these is cell proliferation. SIP is abundantly stored in platelets and released upon their activation, suggesting that SIP plays a pathophysiologic role in vivo. Because the major part of injected SIP was distributed into the liver in mice, we wondered whether the liver would be one of its targets. The effects of SIP on hepatocytes, the major constituent cells in the liver, were examined. Methods & Results: Northern blot analysis revealed the expression of Edg-1 and Edg-5 messenger RNA (mRNA) in cultured rat hepatocytes, in which SIP decreased DNA synthesis induced by hepatocyte growth factor (HGF) or epidermal growth factor (EGF) without affecting total protein synthesis. This inhibitory effect was attenuated by inactivation of small GTPase Rho with C3 exotoxin but not by inactivation of Gi with pertussis toxin. Moreover, in the presence of JTE-013, a newly developed and specific binding antagonist for Edg-5, the inhibitory effect was also cancelled. Finally, the administration of SIP after 70% partial hepatectomy in rats reduced the peak of DNA synthesis in hepatocytes with increased Rho activity. Furthermore, Edg-5 but not Edg-1 mRNA expression was enhanced in hepatocytes 24-72 hours after partial hepatectomy, which coincides with decreasing hepatocyte proliferation. Conclusions: SIP has an antiproliferative property in rat hepatocytes by activating Rho via Edg-5. Our results raise the possibility that SIP is a negative regulator in liver regeneration.

Original languageEnglish
Pages (from-to)459-469
Number of pages11
JournalGastroenterology
Volume124
Issue number2
DOIs
Publication statusPublished - 2003 Feb 1
Externally publishedYes

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Hepatocytes
Hepatectomy
Liver
Genes
sphingosine 1-phosphate
Exotoxins
Messenger RNA
Liver Regeneration
Hepatocyte Growth Factor
Monomeric GTP-Binding Proteins
DNA
Pertussis Toxin
GTP-Binding Proteins
Epidermal Growth Factor
Northern Blotting
Blood Platelets
Cell Proliferation
Ligands
Proteins

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Ikeda, H., Satoh, H., Yanase, M., Inoue, Y., Tomiya, T., Arai, M., ... Fujiwara, K. (2003). Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5. Gastroenterology, 124(2), 459-469. https://doi.org/10.1053/gast.2003.50049

Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5. / Ikeda, Hitoshi; Satoh, Hiroaki; Yanase, Mikio; Inoue, Yukiko; Tomiya, Tomoaki; Arai, Masahiro; Tejima, Kazuaki; Nagashima, Kayo; Maekawa, Hisato; Yahagi, Naohisa; Yatomi, Yutaka; Sakurada, Soutaro; Takuwa, Yoh; Ogata, Itsuro; Kimura, Satoshi; Fujiwara, Kenji.

In: Gastroenterology, Vol. 124, No. 2, 01.02.2003, p. 459-469.

Research output: Contribution to journalArticle

Ikeda, H, Satoh, H, Yanase, M, Inoue, Y, Tomiya, T, Arai, M, Tejima, K, Nagashima, K, Maekawa, H, Yahagi, N, Yatomi, Y, Sakurada, S, Takuwa, Y, Ogata, I, Kimura, S & Fujiwara, K 2003, 'Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5', Gastroenterology, vol. 124, no. 2, pp. 459-469. https://doi.org/10.1053/gast.2003.50049
Ikeda, Hitoshi ; Satoh, Hiroaki ; Yanase, Mikio ; Inoue, Yukiko ; Tomiya, Tomoaki ; Arai, Masahiro ; Tejima, Kazuaki ; Nagashima, Kayo ; Maekawa, Hisato ; Yahagi, Naohisa ; Yatomi, Yutaka ; Sakurada, Soutaro ; Takuwa, Yoh ; Ogata, Itsuro ; Kimura, Satoshi ; Fujiwara, Kenji. / Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5. In: Gastroenterology. 2003 ; Vol. 124, No. 2. pp. 459-469.
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T1 - Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5

AU - Ikeda, Hitoshi

AU - Satoh, Hiroaki

AU - Yanase, Mikio

AU - Inoue, Yukiko

AU - Tomiya, Tomoaki

AU - Arai, Masahiro

AU - Tejima, Kazuaki

AU - Nagashima, Kayo

AU - Maekawa, Hisato

AU - Yahagi, Naohisa

AU - Yatomi, Yutaka

AU - Sakurada, Soutaro

AU - Takuwa, Yoh

AU - Ogata, Itsuro

AU - Kimura, Satoshi

AU - Fujiwara, Kenji

PY - 2003/2/1

Y1 - 2003/2/1

N2 - Background & Aims: Sphingosine 1-phosphate (SIP), a ligand for G protein-coupled endothelial differentiation gene-1 (Edg-1), Edg-3, Edg-5, Edg-6, and Edg-8, elicits a variety of responses by cells. Prominent among these is cell proliferation. SIP is abundantly stored in platelets and released upon their activation, suggesting that SIP plays a pathophysiologic role in vivo. Because the major part of injected SIP was distributed into the liver in mice, we wondered whether the liver would be one of its targets. The effects of SIP on hepatocytes, the major constituent cells in the liver, were examined. Methods & Results: Northern blot analysis revealed the expression of Edg-1 and Edg-5 messenger RNA (mRNA) in cultured rat hepatocytes, in which SIP decreased DNA synthesis induced by hepatocyte growth factor (HGF) or epidermal growth factor (EGF) without affecting total protein synthesis. This inhibitory effect was attenuated by inactivation of small GTPase Rho with C3 exotoxin but not by inactivation of Gi with pertussis toxin. Moreover, in the presence of JTE-013, a newly developed and specific binding antagonist for Edg-5, the inhibitory effect was also cancelled. Finally, the administration of SIP after 70% partial hepatectomy in rats reduced the peak of DNA synthesis in hepatocytes with increased Rho activity. Furthermore, Edg-5 but not Edg-1 mRNA expression was enhanced in hepatocytes 24-72 hours after partial hepatectomy, which coincides with decreasing hepatocyte proliferation. Conclusions: SIP has an antiproliferative property in rat hepatocytes by activating Rho via Edg-5. Our results raise the possibility that SIP is a negative regulator in liver regeneration.

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