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Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis.
J Pharm Sci. 2016 05; 105(5):1779-1789.JP

Abstract

Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1(-/-)) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1(-/-), but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis.

Authors+Show Affiliations

Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Life Science Institute Co. Ltd., Chuo-ku, Tokyo 103-0012, Japan; Customer Support Division, L·S Corporation Co. Ltd., Chuo-ku, Tokyo 103-0013, Japan.Life Science Institute Co. Ltd., Chuo-ku, Tokyo 103-0012, Japan; Customer Support Division, L·S Corporation Co. Ltd., Chuo-ku, Tokyo 103-0013, Japan.Life Science Institute Co. Ltd., Chuo-ku, Tokyo 103-0012, Japan.School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: ykato@p.kanazawa-u.ac.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27020986

Citation

Tang, Yaliang, et al. "Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis." Journal of Pharmaceutical Sciences, vol. 105, no. 5, 2016, pp. 1779-1789.
Tang Y, Masuo Y, Sakai Y, et al. Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis. J Pharm Sci. 2016;105(5):1779-1789.
Tang, Y., Masuo, Y., Sakai, Y., Wakayama, T., Sugiura, T., Harada, R., Futatsugi, A., Komura, T., Nakamichi, N., Sekiguchi, H., Sutoh, K., Usumi, K., Iseki, S., Kaneko, S., & Kato, Y. (2016). Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis. Journal of Pharmaceutical Sciences, 105(5), 1779-1789. https://doi.org/10.1016/j.xphs.2016.02.023
Tang Y, et al. Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis. J Pharm Sci. 2016;105(5):1779-1789. PubMed PMID: 27020986.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis. AU - Tang,Yaliang, AU - Masuo,Yusuke, AU - Sakai,Yoshio, AU - Wakayama,Tomohiko, AU - Sugiura,Tomoko, AU - Harada,Ryuichi, AU - Futatsugi,Azusa, AU - Komura,Takuya, AU - Nakamichi,Noritaka, AU - Sekiguchi,Hirotaka, AU - Sutoh,Keita, AU - Usumi,Koji, AU - Iseki,Shoichi, AU - Kaneko,Shuichi, AU - Kato,Yukio, Y1 - 2016/03/25/ PY - 2015/10/06/received PY - 2015/12/06/revised PY - 2015/12/15/accepted PY - 2016/3/30/entrez PY - 2016/3/30/pubmed PY - 2017/12/5/medline KW - antioxidants KW - induction KW - membrane transporter KW - organic cation transporters (OCT) KW - transporters SP - 1779 EP - 1789 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 105 IS - 5 N2 - Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1(-/-)) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1(-/-), but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/27020986/Localization_of_Xenobiotic_Transporter_OCTN1/SLC22A4_in_Hepatic_Stellate_Cells_and_Its_Protective_Role_in_Liver_Fibrosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(16)00389-0 DB - PRIME DP - Unbound Medicine ER -