{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:15:18Z","timestamp":1791483318471,"version":"4.3.4"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,1,26]]},"abstract":"<jats:p>\n                    \u03b1-Klotho (\u03b1-Kl) and its homolog, \u03b2-Klotho (\u03b2-Kl) are key regulators of mineral homeostasis and bile acid\/cholesterol metabolism, respectively. FGF15\/ humanFGF19, FGF21, and FGF23, members of the FGF19 subfamily, are believed to act as circulating metabolic regulators. Analyses of functional interactions between \u03b1- and \u03b2-Kl and FGF19 factors in wild-type,\n                    <jats:italic>\u03b1-kl<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    , and\n                    <jats:italic>\u03b2-kl<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice revealed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive\/negative feedback actions of \u03b1-Kl, FGF23, and 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D and an analogous regulatory network composed of \u03b2-Kl, FGF15\/humanFGF19, and bile acids that regulate bile acid\/cholesterol metabolism. Contrary to in vitro data, \u03b2-Kl is not essential for FGF21 signaling in adipose tissues in vivo, because (\n                    <jats:italic>i<\/jats:italic>\n                    ) FGF21 signals are transduced in the absence of \u03b2-Kl, (\n                    <jats:italic>ii<\/jats:italic>\n                    ) FGF21 could not be precipitated by \u03b2-Kl, and (\n                    <jats:italic>iii<\/jats:italic>\n                    ) essential phenotypes in\n                    <jats:italic>Fgf21<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice (decreased expressions of\n                    <jats:italic>Hsl<\/jats:italic>\n                    and\n                    <jats:italic>Atgl<\/jats:italic>\n                    in WAT) were not replicated in\n                    <jats:italic>\u03b2-kl<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. These findings suggest the existence of Klotho-independent FGF21 signaling pathway(s) where undefined cofactors are involved. One-to-one functional interactions such as \u03b1-Klotho\/FGF23, \u03b2-Klotho\/FGF15 (humanFGF19), and undefined cofactor\/FGF21 would result in tissue-specific signal transduction of the FGF19 subfamily.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0913986107","type":"journal-article","created":{"date-parts":[[2010,1,8]],"date-time":"2010-01-08T22:07:12Z","timestamp":1262988432000},"page":"1666-1671","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":128,"title":["Relevant use of Klotho in FGF19 subfamily signaling system in vivo"],"prefix":"10.1073","volume":"107","author":[{"given":"Ken-ichi","family":"Tomiyama","sequence":"first","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan;"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi-shi, Saitama 332-0012, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan;"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi-shi, Saitama 332-0012, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itaru","family":"Urakawa","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Laboratories, Kyowa Hakko Kirin Company, Ltd., Takasaki, Gunma 370-1295, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Laboratories, Kyowa Hakko Kirin Company, Ltd., Takasaki, Gunma 370-1295, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan;"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi-shi, Saitama 332-0012, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan;"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi-shi, Saitama 332-0012, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Nabeshima","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan;"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi-shi, Saitama 332-0012, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Odori","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiminori","family":"Hosoda","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuwa","family":"Nakao","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Imura","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan;"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi-shi, Saitama 332-0012, Japan; 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