{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:04:21Z","timestamp":1791187461491,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":304,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006458","name":"Children's Hospital of Philadelphia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose-induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie-matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin- or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling.<\/jats:bold>\n                      <jats:bold>Conclusion<\/jats:bold>\n                      <jats:bold>: Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients. (Hepatology 2014;60:1581\u20131592)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.27284","type":"journal-article","created":{"date-parts":[[2014,7,4]],"date-time":"2014-07-04T22:31:27Z","timestamp":1404513087000},"page":"1581-1592","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":119,"title":["Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition"],"prefix":"10.1097","volume":"60","author":[{"given":"Valerie","family":"Sapp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Gaffney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven F.","family":"EauClaire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randolph P.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-19-20250207","doi-asserted-by":"crossref","first-page":"565576","DOI":"10.1177\/0884533611419668","article-title":"Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy.","volume":"26","author":"Kopec","year":"2011","journal-title":"Nutr Clin Pract"},{"key":"R2-19-20250207","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.1093\/aje\/kws448","article-title":"Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 19881994.","volume":"178","author":"Lazo","year":"2013","journal-title":"Am J Epidemiol"},{"key":"R3-19-20250207","first-page":"18011804","article-title":"Longitudinal trends in obesity in the United States from adolescence to the third decade of life.","volume":"18","author":"GordonLarsen","year":"2010","journal-title":"Obesity"},{"key":"R5-19-20250207","doi-asserted-by":"crossref","first-page":"322329","DOI":"10.1016\/j.acap.2009.04.005","article-title":"Prevalence and trends of severe obesity among US children and adolescents.","volume":"9","author":"Skelton","year":"2009","journal-title":"Acad Pediatr"},{"key":"R7-19-20250207","doi-asserted-by":"crossref","first-page":"597603","DOI":"10.1097\/MPG.0b013e318192d224","article-title":"Trends in nonalcoholic fatty liver diseaserelated hospitalizations in US children, adolescents, and young adults.","volume":"48","author":"Koebnick","year":"2009","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"R8-19-20250207","doi-asserted-by":"crossref","first-page":"1228S12235S","DOI":"10.3945\/jn.108.098277","article-title":"National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.","volume":"139","author":"Marriott","year":"2009","journal-title":"J Nutr"},{"key":"R9-19-20250207","doi-asserted-by":"crossref","first-page":"993999","DOI":"10.1016\/j.jhep.2008.02.011","article-title":"Fructose consumption as a risk factor for nonalcoholic fatty liver disease.","volume":"48","author":"Ouyang","year":"2008","journal-title":"J Hepatol"},{"key":"R10-19-20250207","doi-asserted-by":"crossref","first-page":"19611971","DOI":"10.1002\/hep.23535","article-title":"Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.","volume":"51","author":"Abdelmalek","year":"2010","journal-title":"Hepatology"},{"key":"R11-19-20250207","doi-asserted-by":"crossref","first-page":"9096","DOI":"10.1097\/MPG.0b013e318229da1a","article-title":"Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD.","volume":"54","author":"Vos","year":"2012","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"R12-19-20250207","doi-asserted-by":"crossref","first-page":"20672071","DOI":"10.3945\/jn.109.105858","article-title":"Rats fed fructoseenriched diets have characteristics of nonalcoholic hepatic steatosis.","volume":"139","author":"Kawasaki","year":"2009","journal-title":"J Nutr"},{"key":"R13-19-20250207","doi-asserted-by":"crossref","first-page":"203208","DOI":"10.1016\/j.jnutbio.2011.09.006","article-title":"The role of fructoseenriched diets in mechanisms of nonalcoholic fatty liver disease.","volume":"23","author":"Nomura","year":"2012","journal-title":"J Nutr Biochem"},{"key":"R14-19-20250207","doi-asserted-by":"crossref","first-page":"865875","DOI":"10.1242\/dev.027565","article-title":"TNFalphadependent hepatic steatosis and liver degeneration caused by mutation of zebrafish sadenosylhomocysteine hydrolase.","volume":"136","author":"Matthews","year":"2009","journal-title":"Development"},{"key":"R15-19-20250207","doi-asserted-by":"crossref","first-page":"452462","DOI":"10.1002\/hep.24349","article-title":"Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdiptdeficient zebrafish.","volume":"54","author":"Thakur","year":"2011","journal-title":"Hepatology"},{"key":"R16-19-20250207","first-page":"495508","article-title":"Activating transcription factor 6 plays protective and pathological roles in steatosis due to endoplasmic reticulum stress in zebrafish.","volume":"54","author":"Cinaroglu","year":"2012","journal-title":"Hepatology"},{"key":"R17-19-20250207","doi-asserted-by":"crossref","first-page":"225232","DOI":"10.1007\/s11373-005-9055-5","article-title":"Thioacetamide induced liver damage in zebrafish embryo as a disease model for steatohepatitis.","volume":"13","author":"Amali","year":"2006","journal-title":"J Biomed Sci"},{"key":"R18-19-20250207","first-page":"675682","article-title":"The effect of taurine on hepatic steatosis induced by thioacetamide in zebrafish (Danio rerio).","volume":"57","author":"Hammes","year":"2011","journal-title":"Dig Dis Sci"},{"key":"R19-19-20250207","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/1743-7075-8-88","article-title":"Transcriptome analysis of antifatty liver action by Campari tomato using a zebrafish dietinduced obesity model.","volume":"8","author":"Tainaka","year":"2011","journal-title":"Nutr Metab"},{"key":"R20-19-20250207","first-page":"483491","article-title":"Histochemical detection of lipid droplets in cultured cells.","volume":"931","author":"Suzuki","year":"2013","journal-title":"Methods Mol Biol"},{"key":"R21-19-20250207","doi-asserted-by":"crossref","first-page":"434444","DOI":"10.1016\/j.ydbio.2012.03.009","article-title":"Mutations in vacuolar H()ATPase subunits lead to biliary developmental defects in zebrafish.","volume":"365","author":"Eauclaire","year":"2012","journal-title":"Dev Biol"},{"key":"R22-19-20250207","doi-asserted-by":"crossref","first-page":"229241","DOI":"10.1016\/j.ydbio.2010.12.041","article-title":"Disruption of planar cell polarity activity leads to developmental biliary defects.","volume":"351","author":"Cui","year":"2011","journal-title":"Dev Biol"},{"key":"R23-19-20250207","first-page":"67125","article-title":"Markers in nonalcoholic steatohepatitis.","volume":"61","author":"Armutcu","year":"2013","journal-title":"Adv Clin Chem"},{"key":"R24-19-20250207","doi-asserted-by":"crossref","first-page":"14631466","DOI":"10.1002\/hep.510270601","article-title":"Hepatic steatosis: innocent bystander or guilty party?","volume":"27","author":"Day","year":"1998","journal-title":"Hepatology"},{"issue":"Suppl 2","key":"R25-19-20250207","first-page":"7173","article-title":"Review article: role of oxidative stress in the progression of nonalcoholic steatosis.","volume":"22","author":"Albano","year":"2005","journal-title":"Aliment Pharmacol Ther"},{"key":"R26-19-20250207","first-page":"12131226","article-title":"Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease.","volume":"6","author":"Tsedensodnom","year":"2013","journal-title":"Dis Model Mech"},{"key":"R27-19-20250207","doi-asserted-by":"crossref","first-page":"439448","DOI":"10.1038\/nrm1660","article-title":"Autophagy in metazoans: cell survival in the land of plenty.","volume":"6","author":"Lum","year":"2005","journal-title":"Nat Rev"},{"key":"R29-19-20250207","doi-asserted-by":"crossref","first-page":"e25269","DOI":"10.1371\/journal.pone.0025269","article-title":"GLP1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.","volume":"6","author":"Sharma","year":"2011","journal-title":"PLoS One"},{"key":"R31-19-20250207","doi-asserted-by":"crossref","first-page":"471484","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism.","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell"},{"key":"R33-19-20250207","doi-asserted-by":"crossref","first-page":"11851193","DOI":"10.1007\/s00726-011-0983-2","article-title":"Leucine nutrition in animals and humans: mTOR signaling and beyond.","volume":"41","author":"Li","year":"2011","journal-title":"Amino Acids"},{"key":"R34-19-20250207","first-page":"909915","article-title":"Mammalian target of the rapamycin pathway is involved in nonalcoholic fatty liver disease.","volume":"3","author":"Wang","year":"2010","journal-title":"Mol Med Rep"},{"key":"R35-19-20250207","doi-asserted-by":"crossref","first-page":"993999","DOI":"10.1016\/j.jhep.2013.01.011","article-title":"Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and nonalcoholic fatty liver conditions in mice.","volume":"58","author":"Lin","year":"2013","journal-title":"Journal of hepatology"},{"key":"R36-19-20250207","first-page":"14931501","article-title":"Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis.","volume":"53","author":"Wang","year":"2012","journal-title":"J Lipid Res"},{"key":"R37-19-20250207","doi-asserted-by":"crossref","first-page":"197202","DOI":"10.1016\/j.bbrc.2011.07.038","article-title":"Role of S6K1 in regulation of SREBP1c expression in the liver.","volume":"412","author":"Li","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"R38-19-20250207","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1016\/j.cmet.2011.07.004","article-title":"Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1dependent and independent pathways.","volume":"14","author":"Yecies","year":"2011","journal-title":"Cell Metab"},{"key":"R39-19-20250207","doi-asserted-by":"crossref","first-page":"e18075","DOI":"10.1371\/journal.pone.0018075","article-title":"Tuberous sclerosis complex1 deficiency attenuates dietinduced hepatic lipid accumulation.","volume":"6","author":"Kenerson","year":"2011","journal-title":"PLoS One"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27284","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201411000-00019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T11:50:05Z","timestamp":1738929005000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201411000-00019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.27284","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2014,11]]}}}