title: Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis.
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.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yaliang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Masuo
authors.affiliation: School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Wakayama
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Harada
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Futatsugi
authors.affiliation: School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Komura
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.affiliation: 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.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Sekiguchi
authors.affiliation: 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.
authors.forename: Keita
authors.initials: K
authors.lastname: Sutoh
authors.affiliation: Life Science Institute Co. Ltd., Chuo-ku, Tokyo 103-0012, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Usumi
authors.affiliation: School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iseki
authors.affiliation: School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: ykato@p.kanazawa-u.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D002460:Cell Line; D005260:Female; D057809:HEK293 Cells; D055166:Hepatic Stellate Cells / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000517:prevention & control*; D008565:Membrane Proteins / Q000032:analysis / Q000172:deficiency*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins; D027981:Symporters; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C491659:Slc22a4 protein, mouse; D027981:Symporters; D015262:Xenobiotics
keywords: antioxidants; induction; membrane transporter; organic cation transporters (OCT); transporters