{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:42:57Z","timestamp":1787006577211,"version":"build-2736575974"},"reference-count":23,"publisher":"Informa UK Limited","issue":"5","license":[{"start":{"date-parts":[[2016,5,3]],"date-time":"2016-05-03T00:00:00Z","timestamp":1462233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","award":["25504003"],"award-info":[{"award-number":["25504003"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","award":["25504003"],"award-info":[{"award-number":["25504003"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.tandfonline.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fibroblast growth factor 21 (FGF21) is an endocrine growth factor, a regulator of fatty acids and glucose metabolism. Recently, it has been reported that FGF21 expression is regulated by activating transcription factor 4 (ATF4), a transcription factor activated by various stimuli such as endoplasmic reticulum (ER) stress. ATF4 binds to the amino acid response element (AARE), a binding site for ATF4, in the promoter region of the target genes. The two response elements for ATF4 (AARE1 and AARE2) have been reported in the promoter region of FGF21 gene. In this study, we found a novel response element, located upstream of AARE1 and AARE2, essential for a promoter activation of FGF21. When this DNA sequence, named AARE3, was mutated, the promoter activation by ATF4 or ER stress was strongly decreased. Our results showed that the FGF21 promoter contains three response elements for ATF4, suggesting that FGF21 is a sensitive target of ATF4.<\/jats:p>","DOI":"10.1080\/09168451.2015.1135045","type":"journal-article","created":{"date-parts":[[2016,3,24]],"date-time":"2016-03-24T09:13:19Z","timestamp":1458810799000},"page":"929-934","update-policy":"https:\/\/doi.org\/10.1080\/tandf_crossmark_01","source":"Crossref","is-referenced-by-count":46,"title":["<i>Fibroblast growth factor 21<\/i>\n                    induction by activating transcription factor 4 is regulated through three amino acid response elements in its promoter region"],"prefix":"10.1080","volume":"80","author":[{"given":"Ryuto","family":"Maruyama","sequence":"first","affiliation":[{"name":"Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"301","published-online":{"date-parts":[[2016,5,3]]},"reference":[{"key":"2021033109483776900_CIT0001","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.cmet.2007.05.003","article-title":"Endocrine regulation of the fasting response by PPAR\u03b1-mediated induction of fibroblast growth factor 21","volume":"5","author":"Inagaki","year":"2007","journal-title":"Cell Metab"},{"key":"2021033109483776900_CIT0002","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.cmet.2007.05.002","article-title":"Hepatic fibroblast growth factor 21 is regulated by PPAR\u03b1 and is a key mediator of hepatic lipid metabolism in ketotic states","volume":"5","author":"Badman","year":"2007","journal-title":"Cell Metab"},{"key":"2021033109483776900_CIT0003","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1172\/JCI23606","article-title":"FGF-21 as a novel metabolic regulator","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Invest"},{"key":"2021033109483776900_CIT0004","doi-asserted-by":"publisher","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"2021033109483776900_CIT0005","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.biochi.2012.10.019","article-title":"Fibroblast growth factor 21 is induced by endoplasmic reticulum stress","volume":"95","author":"Schaap","year":"2013","journal-title":"Biochimie"},{"key":"2021033109483776900_CIT0006","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.bbrc.2013.09.026","article-title":"Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation","volume":"440","author":"Kim","year":"2013","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"2021033109483776900_CIT0007","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s00125-014-3475-6","article-title":"Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress","volume":"58","author":"Kim","year":"2015","journal-title":"Diabetologia"},{"key":"2021033109483776900_CIT0008","doi-asserted-by":"publisher","first-page":"29751","DOI":"10.1074\/jbc.M114.565960","article-title":"Fibroblast growth factor 21 is regulated by the IRE1\u03b1-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis","volume":"289","author":"Jiang","year":"2014","journal-title":"J. Biol. Chem"},{"key":"2021033109483776900_CIT0009","doi-asserted-by":"publisher","first-page":"154","DOI":"10.3177\/jnsv.61.154","article-title":"Selective regulation of FGF19 and FGF21 expression by cellular and nutritional stress","volume":"61","author":"Shimizu","year":"2015","journal-title":"J. Nutr. Sci. Vitaminol. (Tokyo)"},{"key":"2021033109483776900_CIT0010","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1042\/BJ20111748","article-title":"Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation","volume":"443","author":"De Sousa-Coelho","year":"2012","journal-title":"Biochem. J"},{"key":"2021033109483776900_CIT0011","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nm.3014","article-title":"Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine","volume":"19","author":"Kim","year":"2013","journal-title":"Nat. Med"},{"key":"2021033109483776900_CIT0012","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: from stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"2021033109483776900_CIT0013","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1126\/science.1128294","article-title":"Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes","volume":"313","author":"Ozcan","year":"2006","journal-title":"Science"},{"key":"2021033109483776900_CIT0014","doi-asserted-by":"publisher","first-page":"24120","DOI":"10.1074\/jbc.M201959200","article-title":"ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene","volume":"277","author":"Siu","year":"2002","journal-title":"J. Biol. Chem"},{"key":"2021033109483776900_CIT0015","doi-asserted-by":"publisher","first-page":"50829","DOI":"10.1074\/jbc.M409173200","article-title":"Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region\/leucine zipper transcription factors as well as localized histone acetylation","volume":"279","author":"Chen","year":"2004","journal-title":"J. Biol. Chem"},{"key":"2021033109483776900_CIT0016","doi-asserted-by":"publisher","first-page":"5288","DOI":"10.1074\/jbc.M311862200","article-title":"Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation","volume":"279","author":"Averous","year":"2004","journal-title":"J. Biol. Chem"},{"key":"2021033109483776900_CIT0017","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1042\/BJ20121393","article-title":"FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress","volume":"450","author":"Shimizu","year":"2013","journal-title":"Biochem. J"},{"key":"2021033109483776900_CIT0018","doi-asserted-by":"publisher","first-page":"24714","DOI":"10.1074\/jbc.274.35.24714","article-title":"Sterol regulatory element-binding protein negatively regulates microsomal triglyceride transfer protein gene transcription","volume":"274","author":"Sato","year":"1999","journal-title":"J. Biol. Chem"},{"key":"2021033109483776900_CIT0019","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/S0092-8674(00)00062-3","article-title":"Targeted disruption of the nuclear receptor FXR\/BAR impairs bile acid and lipid homeostasis","volume":"102","author":"Sinal","year":"2000","journal-title":"Cell"},{"key":"2021033109483776900_CIT0020","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1042\/BJ20061261","article-title":"Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation","volume":"401","author":"Pan","year":"2007","journal-title":"Biochem. J"},{"key":"2021033109483776900_CIT0021","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.cmet.2013.08.005","article-title":"The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes","volume":"18","author":"Gaich","year":"2013","journal-title":"Cell Metab"},{"key":"2021033109483776900_CIT0022","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1210\/en.2006-1168","article-title":"The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21","volume":"148","author":"Kharitonenkov","year":"2007","journal-title":"Endocrinology"},{"key":"2021033109483776900_CIT0023","doi-asserted-by":"publisher","first-page":"439","DOI":"10.3945\/an.113.003798","article-title":"PPAR-\u03b1 as a key nutritional and environmental sensor for metabolic adaptation","volume":"4","author":"Contreras","year":"2013","journal-title":"Adv. Nutr"}],"container-title":["Bioscience, Biotechnology, and Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bbb\/article-pdf\/80\/5\/929\/36828370\/bbb0929.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/bbb\/article-pdf\/80\/5\/929\/36828370\/bbb0929.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T07:50:20Z","timestamp":1654588220000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bbb\/article\/80\/5\/929\/5939000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,3]]},"references-count":23,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2016,5,3]]},"published-print":{"date-parts":[[2016,5,3]]}},"URL":"https:\/\/doi.org\/10.1080\/09168451.2015.1135045","relation":{},"ISSN":["0916-8451","1347-6947"],"issn-type":[{"value":"0916-8451","type":"print"},{"value":"1347-6947","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,5,3]]},"published":{"date-parts":[[2016,5,3]]},"assertion":[{"value":"The publishing and review policy for this title is described in its Aims & Scope.","order":1,"name":"peerreview_statement","label":"Peer Review Statement"},{"value":"http:\/\/www.tandfonline.com\/action\/journalInformation?show=aimsScope&journalCode=tbbb20","URL":"http:\/\/www.tandfonline.com\/action\/journalInformation?show=aimsScope&journalCode=tbbb20","order":2,"name":"aims_and_scope_url","label":"Aim & Scope"},{"value":"2015-11-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-12-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-03-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}