{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:28:58Z","timestamp":1791242938968,"version":"4.1.0"},"reference-count":43,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:p>Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5\u2032 regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.<\/jats:p>","DOI":"10.1042\/bj20111748","type":"journal-article","created":{"date-parts":[[2012,1,12]],"date-time":"2012-01-12T12:36:36Z","timestamp":1326371796000},"page":"165-171","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":232,"title":["Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation"],"prefix":"10.1042","volume":"443","author":[{"given":"Ana\u00a0Lu\u00edsa","family":"De Sousa-Coelho","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB), Av. Joan XXIII s\/n, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro\u00a0F.","family":"Marrero","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB), Av. Joan XXIII s\/n, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Haro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB), Av. Joan XXIII s\/n, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2012,3,14]]},"reference":[{"key":"2021112217280559600_B1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tem.2009.05.008","article-title":"ATF4-dependent transcription mediates signaling of amino acid limitation","volume":"20","author":"Kilberg","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"2021112217280559600_B2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.cmet.2007.01.001","article-title":"The GCN2 eIF2\u03b1 kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid","volume":"5","author":"Guo","year":"2007","journal-title":"Cell Metab."},{"key":"2021112217280559600_B3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.2337\/db09-0929","article-title":"Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue","volume":"59","author":"Cheng","year":"2010","journal-title":"Diabetes"},{"key":"2021112217280559600_B4","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1210\/me.2011-0028","article-title":"Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system","volume":"25","author":"Cheng","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"2021112217280559600_B5","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1126\/science.1104882","article-title":"Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex","volume":"307","author":"Hao","year":"2005","journal-title":"Science"},{"key":"2021112217280559600_B6","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cmet.2005.03.004","article-title":"The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores","volume":"1","author":"Maurin","year":"2005","journal-title":"Cell Metab."},{"key":"2021112217280559600_B7","doi-asserted-by":"crossref","first-page":"11269","DOI":"10.1073\/pnas.0400541101","article-title":"Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells","volume":"101","author":"Vattem","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112217280559600_B8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1083\/jcb.200408003","article-title":"Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response","volume":"167","author":"Lu","year":"2004","journal-title":"J. Cell Biol."},{"key":"2021112217280559600_B9","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.biocel.2007.01.020","article-title":"Activating transcription factor 4","volume":"40","author":"Ameri","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021112217280559600_B10","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1210\/me.2009-0345","article-title":"The transcription factor ATF4 promotes skeletal myofiber atrophy during fasting","volume":"24","author":"Ebert","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"2021112217280559600_B11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0167-4781(00)00067-1","article-title":"Identification of a novel FGF, FGF-21, preferentially expressed in the liver","volume":"1492","author":"Nishimura","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112217280559600_B12","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1053\/j.gastro.2009.07.064","article-title":"Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice","volume":"137","author":"Johnson","year":"2009","journal-title":"Gastroenterology"},{"key":"2021112217280559600_B13","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1016\/j.febslet.2008.10.021","article-title":"FGF21 is an Akt-regulated myokine","volume":"582","author":"Izumiya","year":"2008","journal-title":"FEBS Lett."},{"key":"2021112217280559600_B14","doi-asserted-by":"crossref","first-page":"12983","DOI":"10.1074\/jbc.M110.215889","article-title":"Thermogenic activation induces FGF21 expression and release in brown adipose tissue","volume":"286","author":"Hondares","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B15","doi-asserted-by":"crossref","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":"2021112217280559600_B16","doi-asserted-by":"crossref","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":"2021112217280559600_B17","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.cmet.2008.06.014","article-title":"The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPAR\u03b1 activation in man","volume":"8","author":"G\u00e4lman","year":"2008","journal-title":"Cell Metab."},{"key":"2021112217280559600_B18","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.bbrc.2007.06.068","article-title":"PPAR\u03b1 is a key regulator of hepatic FGF21","volume":"360","author":"Lund\u00e5sen","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112217280559600_B19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.cmet.2007.05.010","article-title":"FGF21: a missing link in the biology of fasting","volume":"5","author":"Reitman","year":"2007","journal-title":"Cell Metab."},{"key":"2021112217280559600_B20","doi-asserted-by":"crossref","first-page":"20423","DOI":"10.1074\/jbc.M111.235044","article-title":"Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line","volume":"286","author":"Vil\u00e0-Brau","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B21","doi-asserted-by":"crossref","first-page":"9774","DOI":"10.1073\/pnas.86.24.9774","article-title":"Transcriptional activity of the human thymidine kinase gene determined by a method using the polymerase chain reaction and an intron-specific probe","volume":"86","author":"Lipson","year":"1989","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112217280559600_B22","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1073\/pnas.0807611106","article-title":"ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells","volume":"106","author":"Wang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112217280559600_B23","doi-asserted-by":"crossref","first-page":"18767","DOI":"10.1016\/S0021-9258(17)32234-2","article-title":"Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids","volume":"269","author":"Rodr\u00edguez","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B24","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.bbrc.2004.05.035","article-title":"Different ways to regulate the PPAR\u03b1 stability","volume":"319","author":"Blanquart","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112217280559600_B25","doi-asserted-by":"crossref","first-page":"3854","DOI":"10.1016\/S0021-9258(19)45112-0","article-title":"Reversible inhibition by histidinol of protein synthesis in human cells at the activation of histidine","volume":"247","author":"Hansen","year":"1972","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B26","doi-asserted-by":"crossref","first-page":"14189","DOI":"10.1074\/jbc.M413660200","article-title":"Phosphorylation of the \u03b1-subunit of the eukaryotic initiation factor-2 (eIF2\u03b1) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition","volume":"280","author":"Jiang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B27","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1124\/mol.108.044826","article-title":"Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor \u03b3 and altered metabolic states","volume":"74","author":"Muise","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"2021112217280559600_B28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jcp.20847","article-title":"Molecular determinants of FGF-21 activity-synergy and cross-talk with PPAR\u03b3 signaling","volume":"210","author":"Moyers","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"2021112217280559600_B29","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1128\/MCB.00992-07","article-title":"Identification of a domain within peroxisome proliferator-activated receptor \u03b3 regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes","volume":"28","author":"Wang","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2021112217280559600_B30","doi-asserted-by":"crossref","first-page":"22510","DOI":"10.1073\/pnas.0912533106","article-title":"PGC-1\u03b1 negatively regulates hepatic FGF21 expression by modulating the heme\/Rev-Erb\u03b1 axis","volume":"106","author":"Estall","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112217280559600_B31","doi-asserted-by":"crossref","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":"2021112217280559600_B32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1042\/BJ20060941","article-title":"A feedback transcriptional mechanism controls the level of the arginine\/lysine transporter cat-1 during amino acid starvation","volume":"402","author":"Lopez","year":"2007","journal-title":"Biochem. J."},{"key":"2021112217280559600_B33","doi-asserted-by":"crossref","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":"2021112217280559600_B34","doi-asserted-by":"crossref","first-page":"34609","DOI":"10.1074\/jbc.M507802200","article-title":"Interaction of RNA-binding proteins HuR and AUF1 with the human ATF3 mRNA 3\u2032-untranslated region regulates its amino acid limitation-induced stabilization","volume":"280","author":"Pan","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B35","doi-asserted-by":"crossref","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":"2021112217280559600_B36","doi-asserted-by":"crossref","first-page":"35106","DOI":"10.1074\/jbc.M806874200","article-title":"C\/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene","volume":"283","author":"Su","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021112217280559600_B37","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.2337\/db09-0335","article-title":"Atf4 regulates obesity, glucose homeostasis, and energy expenditure","volume":"58","author":"Seo","year":"2009","journal-title":"Diabetes"},{"key":"2021112217280559600_B38","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.molcel.2010.09.023","article-title":"Autophagy and the integrated stress response","volume":"40","author":"Kroemer","year":"2010","journal-title":"Mol. Cell"},{"key":"2021112217280559600_B39","doi-asserted-by":"crossref","first-page":"3632","DOI":"10.1093\/jn\/132.12.3632","article-title":"Dietary protein quantity and quality affect rat hepatic gene expression","volume":"132","author":"Endo","year":"2002","journal-title":"J. Nutr."},{"key":"2021112217280559600_B40","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.mce.2011.05.003","article-title":"The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes","volume":"342","author":"Zhang","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021112217280559600_B41","doi-asserted-by":"crossref","first-page":"746","DOI":"10.2337\/db10-1246","article-title":"Leucine deprivation increases hepatic insulin sensitivity via GCN2\/mTOR\/S6K1 and AMPK pathways","volume":"60","author":"Xiao","year":"2011","journal-title":"Diabetes"},{"key":"2021112217280559600_B42","doi-asserted-by":"crossref","first-page":"901S","DOI":"10.3945\/ajcn.110.001941","article-title":"Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis","volume":"93","author":"Domouzoglou","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"2021112217280559600_B43","doi-asserted-by":"crossref","first-page":"12553","DOI":"10.1073\/pnas.1006962107","article-title":"Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK\u2013SIRT1\u2013PGC-1\u03b1 pathway","volume":"107","author":"Chau","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/443\/1\/165\/666457\/bj4430165.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/443\/1\/165\/666457\/bj4430165.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T01:18:25Z","timestamp":1637630305000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/443\/1\/165\/80314\/Activating-transcription-factor-4-dependent"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3,14]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,4,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20111748","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,3,14]]}}}