{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:25:10Z","timestamp":1792182310338,"version":"4.4.0"},"reference-count":53,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,5,1]]},"abstract":"<jats:p>VPA (valproic acid), a short-chain fatty acid that is a HDAC (histone deacetylase) inhibitor, is known to suppress adipogenesis. In the present study, we identified the molecular mechanism of VPA-mediated suppression of adipogenesis in adipocytes. VPA suppressed the accumulation of intracellular triacylglycerol. The expression levels of PPAR\u03b3 (peroxisome-proliferator-activated receptor \u03b3) and C\/EBP\u03b1 (CCAAT\/enhancer-binding protein \u03b1), which are key regulators of adipogenesis, as well as the expression of SCD (stearoyl-CoA desaturase), were decreased by the treatment with VPA. Moreover, glycerol release was decreased in the VPA-treated cells, even though the transcription levels of ATGL (adipose triacylglycerol lipase), HSL (hormone-sensitive lipase) and MGL (monoacylglycerol lipase), all of which are involved in lipolysis, were elevated by the treatment with VPA. It is noteworthy that the expression level of FAS (fatty acid synthase) was significantly suppressed when the cells were cultured in medium containing VPA. Furthermore, VPA-mediated suppression of the accumulation of the intracellular triacylglycerols was prevented by the treatment with palmitic acid, a major product of FAS. The results of promoter-luciferase and chromatin immunoprecipitation assays demonstrated that USF1(upstream stimulating factor 1) bound to the E-box of the promoter region of the FAS gene. In addition, the expression of USF1 was decreased by the treatment with VPA. siRNA-mediated knockdown of the expression of the USF1 gene repressed adipogenesis along with the decreased expression of the FAS gene. The overexpression of USF1 enhanced both adipogenesis and the expression of FAS in VPA-treated cells. These results indicate that VPA suppressed adipogenesis through the down-regulation of USF1-activated fatty acid synthesis in adipocytes.<\/jats:p>","DOI":"10.1042\/bj20131476","type":"journal-article","created":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T04:22:29Z","timestamp":1392178949000},"page":"489-503","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Suppression of adipogenesis by valproic acid through repression of USF1-activated fatty acid synthesis in adipocytes"],"prefix":"10.1042","volume":"459","author":[{"given":"Miki","family":"Yuyama","sequence":"first","affiliation":[{"name":"Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko","family":"Fujimori","sequence":"additional","affiliation":[{"name":"Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2014,4,11]]},"reference":[{"key":"2021112215533795500_B1","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1210\/jc.2004-0395","article-title":"Adipose tissue as an endocrine organ","volume":"89","author":"Kershaw","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021112215533795500_B2","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0092-8674(01)00240-9","article-title":"Obesity and the regulation of energy balance","volume":"104","author":"Spiegelman","year":"2001","journal-title":"Cell"},{"key":"2021112215533795500_B3","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1016\/j.febslet.2006.04.028","article-title":"The metabolic syndrome and adipocytokines","volume":"580","author":"Matsuzawa","year":"2006","journal-title":"FEBS Lett."},{"key":"2021112215533795500_B4","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1161\/01.RES.0000163635.62927.34","article-title":"Adipose tissue, inflammation, and cardiovascular disease","volume":"96","author":"Berg","year":"2005","journal-title":"Circ. Res."},{"key":"2021112215533795500_B5","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nrd1930","article-title":"Epigenetic therapy of cancer: past, present and future","volume":"5","author":"Yoo","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"2021112215533795500_B6","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s00253-007-0911-2","article-title":"Histone deacetylases: an important class of cellular regulators with a variety of functions","volume":"75","author":"Hildmann","year":"2007","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"2021112215533795500_B7","doi-asserted-by":"crossref","first-page":"340","DOI":"10.2741\/3691","article-title":"HDACi: going through the mechanisms","volume":"16","author":"Wanczyk","year":"2011","journal-title":"Front Biosci."},{"key":"2021112215533795500_B8","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/j.ejmech.2010.02.030","article-title":"Inside HDAC with HDAC inhibitors","volume":"45","author":"Bertrand","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"2021112215533795500_B9","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.2174\/092986707782360088","article-title":"Valproate and neuroendocrine changes in relation to women treated for epilepsy and bipolar disorder: a review","volume":"14","author":"Reynolds","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"2021112215533795500_B10","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2174\/1568011023353921","article-title":"Histone deacetylase inhibitors and anticancer therapy","volume":"2","author":"Kouraklis","year":"2002","journal-title":"Curr. Med. Chem. Anticancer Agents"},{"key":"2021112215533795500_B11","doi-asserted-by":"crossref","first-page":"18851","DOI":"10.1074\/jbc.M312795200","article-title":"Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis","volume":"279","author":"Lagace","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B12","doi-asserted-by":"crossref","first-page":"14663","DOI":"10.1074\/jbc.M109.081679","article-title":"Redundant control of adipogenesis by histone deacetylases 1 and 2","volume":"285","author":"Haberland","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B13","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nrc2222","article-title":"Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis","volume":"7","author":"Menendez","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"2021112215533795500_B14","doi-asserted-by":"crossref","first-page":"5378","DOI":"10.1073\/pnas.1002588108","article-title":"Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes","volume":"108","author":"Wu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215533795500_B15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/JCI1411","article-title":"Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1\/SREBP1","volume":"101","author":"Kim","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2021112215533795500_B16","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3177\/jnsv.49.40","article-title":"Hormonal and nutritional regulation of lipogenic enzyme mRNA levels in rat primary white and brown adipocytes","volume":"49","author":"Freake","year":"2003","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"2021112215533795500_B17","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1753-4887.1996.tb03886.x","article-title":"Nutritional and hormonal regulation of fatty acid synthase","volume":"54","author":"Wolf","year":"1996","journal-title":"Nutr. Rev."},{"key":"2021112215533795500_B18","doi-asserted-by":"crossref","first-page":"E884","DOI":"10.1152\/ajpendo.90438.2008","article-title":"Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3 genomic and nongenomic actions","volume":"295","author":"Radenne","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2021112215533795500_B19","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1042\/BJ20061722","article-title":"Polyunsaturated fatty acid suppression of fatty acid synthase (FASN): evidence for dietary modulation of NF-Y binding to the Fasn promoter by SREBP-1c","volume":"402","author":"Teran-Garcia","year":"2007","journal-title":"Biochem. J."},{"key":"2021112215533795500_B20","doi-asserted-by":"crossref","first-page":"e44698","DOI":"10.1371\/journal.pone.0044698","article-title":"Synergistic suppression of early phase of adipogenesis by microsomal PGE synthase-1 (PTGES1)-produced PGE2 and aldo-keto reductase 1B3-produced PGF2\u03b1","volume":"7","author":"Fujimori","year":"2012","journal-title":"PLoS ONE"},{"key":"2021112215533795500_B21","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1074\/jbc.M109.077164","article-title":"Suppression of adipocyte differentiation by aldo-keto reductase 1B3 acting as prostaglandin F2\u03b1 synthase","volume":"285","author":"Fujimori","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1091\/mbc.e11-07-0623","article-title":"Rapid degradation of cyclooxygenase-1 and hematopoietic prostaglandin D synthase through ubiquitin-proteasome system in response to intracellular calcium level","volume":"23","author":"Yazaki","year":"2012","journal-title":"Mol. Biol. Cell."},{"key":"2021112215533795500_B23","doi-asserted-by":"crossref","first-page":"13346","DOI":"10.1021\/jf203490a","article-title":"Antiadipogenic effect of dietary apigenin through activation of AMPK in 3T3-L1 cells","volume":"59","author":"Ono","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"2021112215533795500_B24","doi-asserted-by":"crossref","first-page":"E1461","DOI":"10.1152\/ajpendo.00623.2011","article-title":"Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPAR\u03b3 in 3T3-L1 cells","volume":"302","author":"Kobayashi","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2021112215533795500_B25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.gene.2007.04.029","article-title":"Cooperative activation of lipocalin-type prostaglandin D synthase gene expression by activator protein-2\u03b2 in proximal promoter and upstream stimulatory factor 1 within intron 4\u00a0in human brain-derived TE671 cells","volume":"397","author":"Fujimori","year":"2007","journal-title":"Gene"},{"key":"2021112215533795500_B26","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1158\/0008-5472.CAN-03-0799","article-title":"Histone deacetylase is a target of valproic acid-mediated cellular differentiation","volume":"64","author":"Gurvich","year":"2004","journal-title":"Cancer Res."},{"key":"2021112215533795500_B27","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/BF00428553","article-title":"Sodium valproate: effects on social behaviour and physical development in the mouse","volume":"83","author":"Chapman","year":"1984","journal-title":"Psychopharmacology"},{"key":"2021112215533795500_B28","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1042\/bj2710675","article-title":"Molecular cloning of the mammalian fatty acid synthase gene and identification of the promoter region","volume":"271","author":"Amy","year":"1990","journal-title":"Biochem. J."},{"key":"2021112215533795500_B29","doi-asserted-by":"crossref","first-page":"5896","DOI":"10.1128\/MCB.23.16.5896-5907.2003","article-title":"Occupancy and function of the \u2212150 sterol regulatory element and \u221265 E-box in nutritional regulation of the fatty acid synthase gene in living animals","volume":"23","author":"Latasa","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"2021112215533795500_B30","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.bbrc.2007.01.008","article-title":"Upstream stimulatory factors regulate the C\/EBP\u03b1 gene during differentiation of 3T3-L1 preadipocytes","volume":"354","author":"Kim","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112215533795500_B31","doi-asserted-by":"crossref","first-page":"27836","DOI":"10.1074\/jbc.M111.262964","article-title":"Histone deacetylase 9 is a negative regulator of adipogenic differentiation","volume":"286","author":"Chatterjee","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B32","doi-asserted-by":"crossref","first-page":"5453","DOI":"10.1074\/jbc.M610566200","article-title":"Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter","volume":"282","author":"Griffin","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B33","doi-asserted-by":"crossref","first-page":"26367","DOI":"10.1074\/jbc.272.42.26367","article-title":"Upstream stimulatory factor binding to the E-box at \u221265 is required for insulin regulation of the fatty acid synthase promoter","volume":"272","author":"Wang","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B34","doi-asserted-by":"crossref","first-page":"916","DOI":"10.2527\/2004.823916x","article-title":"Role of fatty acids in adipocyte growth and development","volume":"82","author":"Azain","year":"2004","journal-title":"J. Anim. Sci."},{"key":"2021112215533795500_B35","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/978-1-4757-2670-1_12","article-title":"Regulation of gene expression in adipose cells by polyunsaturated fatty acids","volume":"422","author":"Bernlohr","year":"1997","journal-title":"Adv. Exp. Med. Biol."},{"key":"2021112215533795500_B36","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.sbi.2008.09.008","article-title":"The multienzyme architecture of eukaryotic fatty acid synthases","volume":"18","author":"Leibundgut","year":"2008","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2021112215533795500_B37","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1073\/pnas.042683699","article-title":"Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice","volume":"99","author":"Kumar","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215533795500_B38","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1126\/science.288.5475.2379","article-title":"Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors","volume":"288","author":"Loftus","year":"2000","journal-title":"Science"},{"key":"2021112215533795500_B39","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.bbrc.2005.01.067","article-title":"Inhibition of fatty acid synthase prevents preadipocyte differentiation","volume":"328","author":"Schmid","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112215533795500_B40","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1600-0749.2005.00262.x","article-title":"Upstream stimulating factors: highly versatile stress-responsive transcription factors","volume":"18","author":"Corre","year":"2005","journal-title":"Pigment Cell Res."},{"key":"2021112215533795500_B41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1368-504X.2004.00374.x","article-title":"Searching for genes in diabetes and the metabolic syndrome","volume":"143","author":"Hitman","year":"2004","journal-title":"Int. J. Clin. Pract."},{"key":"2021112215533795500_B42","doi-asserted-by":"crossref","first-page":"5356","DOI":"10.1210\/jc.2005-0399","article-title":"Upstream transcription factor-1 gene polymorphism is associated with increased adipocyte lipolysis","volume":"90","author":"Hoffstedt","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021112215533795500_B43","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1161\/ATVBAHA.112.245639","article-title":"Potential role of upstream stimulatory factor 1 gene variant in familial combined hyperlipidemia and related disorders","volume":"32","author":"Auer","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021112215533795500_B44","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3346\/jkms.2008.23.1.83","article-title":"Body mass index is associated with USF1 haplotype in Korean premenopausal women","volume":"23","author":"Lee","year":"2008","journal-title":"J. Korean Med. Sci."},{"key":"2021112215533795500_B45","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1101\/gad.12.5.599","article-title":"Histone acetylation and transcriptional regulatory mechanisms","volume":"12","author":"Struhl","year":"1998","journal-title":"Genes Dev."},{"key":"2021112215533795500_B46","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells","volume":"20","author":"Gottlicher","year":"2001","journal-title":"EMBO J."},{"key":"2021112215533795500_B47","doi-asserted-by":"crossref","first-page":"36734","DOI":"10.1074\/jbc.M101287200","article-title":"Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen","volume":"276","author":"Phiel","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B48","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1158\/0008-5472.CAN-03-0799","article-title":"Histone deacetylase is a target of valproic acid-mediated cellular differentiation","volume":"64","author":"Gurvich","year":"2004","journal-title":"Cancer Res."},{"key":"2021112215533795500_B49","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/0026-0495(92)90061-E","article-title":"Metabolic changes during treatment with valproate in humans: implication for untoward weight gain","volume":"41","author":"Breum","year":"1992","journal-title":"Metabolism"},{"key":"2021112215533795500_B50","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1177\/0269881108091595","article-title":"Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial","volume":"23","author":"Martin","year":"2009","journal-title":"J. Psychopharmacol."},{"key":"2021112215533795500_B51","doi-asserted-by":"crossref","first-page":"6608","DOI":"10.1074\/jbc.M508982200","article-title":"Down-regulation of histone deacetylases stimulates adipocyte differentiation","volume":"281","author":"Yoo","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112215533795500_B52","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1093\/emboj\/cdg218","article-title":"Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex","volume":"22","author":"Wiper-Bergeron","year":"2003","journal-title":"EMBO J."},{"key":"2021112215533795500_B53","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S1534-5807(02)00360-X","article-title":"The retinoblastoma-histone deacetylase 3 complex inhibits PPAR\u03b3 and adipocyte differentiation","volume":"3","author":"Fajas","year":"2002","journal-title":"Dev. Cell"}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/459\/3\/489\/678355\/bj4590489.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/459\/3\/489\/678355\/bj4590489.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T17:30:03Z","timestamp":1637602203000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/459\/3\/489\/46548\/Suppression-of-adipogenesis-by-valproic-acid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,11]]},"references-count":53,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,5,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20131476","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,11]]}}}