{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:55:44Z","timestamp":1791888944943,"version":"4.3.4"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,4,22]],"date-time":"2015-04-22T00:00:00Z","timestamp":1429660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2015,4,22]],"date-time":"2015-04-22T00:00:00Z","timestamp":1429660800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,7]]},"abstract":"<jats:p>\n                    The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress\u2010mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up\u2010regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high\u2010fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2\u2010mediated up\u2010regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up\u2010regulation.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    Sphk2 is transcriptionally up\u2010regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2015;62:135\u2010146)\n                  <\/jats:p>","DOI":"10.1002\/hep.27804","type":"journal-article","created":{"date-parts":[[2015,3,24]],"date-time":"2015-03-24T14:17:30Z","timestamp":1427206650000},"page":"135-146","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":108,"title":["Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice"],"prefix":"10.1097","volume":"62","author":[{"given":"Su\u2010Yeon","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Life Science,Gachon University,Sungnam,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u2010Kyung","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Life Science,Gachon University,Sungnam,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo\u2010Rahm","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Life Science,Gachon University,Sungnam,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soon\u2010Mi","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Food Science and Technology,Sejong University,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae","family":"Sung Lee","sequence":"additional","affiliation":[{"name":"Lee Gil Ya Cancer and Diabetes Institute, Gachon University,Incheon,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Lee Gil Ya Cancer and Diabetes Institute, Gachon University,Incheon,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol","family":"Soo Choi","sequence":"additional","affiliation":[{"name":"Lee Gil Ya Cancer and Diabetes Institute, Gachon University,Incheon,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo\u2010Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology,Functional Genomics Institute, School of Medicine, Konkuk University,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae\u2010Sik","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Life Science,Gachon University,Sungnam,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,4,22]]},"reference":[{"key":"hep27804-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00125-009-1588-0","article-title":"HOMA insulin sensitivity index and the risk of all\u2010cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study","volume":"53","year":"2010","journal-title":"Diabetologia"},{"key":"hep27804-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1093\/eurheartj\/ehp317","article-title":"Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention","volume":"31","year":"2010","journal-title":"Eur Heart J"},{"key":"hep27804-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1177\/1479164109338774","article-title":"Review article: left ventricular dysfunction and heart failure in metabolic syndrome and diabetes without overt coronary artery disease\u2014do we need to screen our patients?","volume":"6","year":"2009","journal-title":"Diab Vasc Dis Res"},{"key":"hep27804-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"G194","DOI":"10.1152\/ajpgi.00413.2005","article-title":"Lipid metabolism and liver inflammation. 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