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To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, <jats:italic>Creb3l3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to <jats:italic>Ppara<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than <jats:italic>Ppara<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice suggesting importance of adipose PPAR\u03b1 for supply of FFA and hyperlipidemia in <jats:italic>Creb3l3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPAR\u03b1. Furthermore, as KD-fed <jats:italic>Creb3l3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD.<\/jats:p>","DOI":"10.1038\/srep39182","type":"journal-article","created":{"date-parts":[[2016,12,17]],"date-time":"2016-12-17T06:41:40Z","timestamp":1481956900000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPAR\u03b1"],"prefix":"10.1038","volume":"6","author":[{"given":"Yoshimi","family":"Nakagawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoi","family":"Satoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Tezuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-iee","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Takei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Iwasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Yatoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Yahagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasumasa","family":"Iwasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohito","family":"Sone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Matsuzaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Shimano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,12,16]]},"reference":[{"key":"BFsrep39182_CR1","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1002\/j.1460-2075.1992.tb05072.x","volume":"11","author":"JD Tugwood","year":"1992","unstructured":"Tugwood, J. 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