{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:46:05Z","timestamp":1791276365030,"version":"4.1.0"},"reference-count":39,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,1,1]]},"abstract":"<jats:p>By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.<\/jats:p>","DOI":"10.1210\/en.2012-1725","type":"journal-article","created":{"date-parts":[[2012,11,17]],"date-time":"2012-11-17T04:45:00Z","timestamp":1353127500000},"page":"36-44","source":"Crossref","is-referenced-by-count":84,"title":["The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats"],"prefix":"10.1210","volume":"154","author":[{"given":"Derek M.","family":"Erion","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"Cellular and Molecular Physiology (D.M.E., G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"Howard Hughes Medical Institute (D.M.E., M.K., J.D., G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violetta","family":"Popov","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Hsiao","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Vatner","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kisha","family":"Mitchell","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute (D.M.E., M.K., J.D., G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"Department of Pathology (K.M.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Yonemitsu","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Nagai","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Kahn","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P.","family":"Gillum","sequence":"first","affiliation":[{"name":"Department of Neurology (M.P.G.), University of Iowa Carver College of Medicine, Iowa City, Iowa 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianying","family":"Dong","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"Howard Hughes Medical Institute (D.M.E., M.K., J.D., G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan F.","family":"Murray","sequence":"first","affiliation":[{"name":"Isis Pharmaceuticals (S.F.M., V.P.M., S.B.), Carlsbad, California 92008"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vara Prasad","family":"Manchem","sequence":"first","affiliation":[{"name":"Isis Pharmaceuticals (S.F.M., V.P.M., S.B.), Carlsbad, California 92008"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Bhanot","sequence":"first","affiliation":[{"name":"Isis Pharmaceuticals (S.F.M., V.P.M., S.B.), Carlsbad, California 92008"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Cline","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald I.","family":"Shulman","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"Cellular and Molecular Physiology (D.M.E., G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"Howard Hughes Medical Institute (D.M.E., M.K., J.D., G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varman T.","family":"Samuel","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (D.M.E., V.P., J.J.H., D.V., S.Y., Y.N., G.W.C., G.I.S., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06510"},{"name":"West Haven Veterans Affairs Medical Center (V.T.S.), West Haven, Connecticut 06516"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071612403515100_B1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.tem.2010.10.003","article-title":"Fructose induced lipogenesis: from sugar to fat to insulin resistance.","volume":"22","author":"Samuel","year":"2011","journal-title":"Trends Endocrinol Metab"},{"key":"2020071612403515100_B2","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1093\/ajcn\/79.4.537","article-title":"Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.","volume":"79","author":"Bray","year":"2004","journal-title":"Am J Clin Nutr"},{"key":"2020071612403515100_B3","doi-asserted-by":"crossref","first-page":"E1180","DOI":"10.1152\/ajpendo.00471.2001","article-title":"Amelioration of high fructose-induced metabolic derangements by activation of PPAR\u03b1.","volume":"282","author":"Nagai","year":"2002","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612403515100_B4","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1210\/jc.2010-2007","article-title":"A dual sugar challenge test for lipogenic sensitivity to dietary fructose.","volume":"96","author":"Hudgins","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612403515100_B5","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1172\/JCI37385","article-title":"Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight\/obese humans.","volume":"119","author":"Stanhope","year":"2009","journal-title":"J Clin Invest"},{"key":"2020071612403515100_B6","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.cmet.2009.01.011","article-title":"The role of peroxisome proliferator-activated receptor \u03b3 coactivator-1\u03b2 in the pathogenesis of fructose-induced insulin resistance.","volume":"9","author":"Nagai","year":"2009","journal-title":"Cell metabolism"},{"key":"2020071612403515100_B7","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nm0410-400","article-title":"Diacylglycerol-mediated insulin resistance.","volume":"16","author":"Erion","year":"2010","journal-title":"Nat Med"},{"key":"2020071612403515100_B8","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1172\/JCI30400","article-title":"Inhibition of protein kinase C\u03f5 prevents hepatic insulin resistance in nonalcoholic fatty liver disease.","volume":"117","author":"Samuel","year":"2007","journal-title":"J Clin Invest"},{"key":"2020071612403515100_B9","doi-asserted-by":"crossref","first-page":"16381","DOI":"10.1073\/pnas.1113359108","article-title":"Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease.","volume":"108","author":"Kumashiro","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612403515100_B10","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1126\/science.1158042","article-title":"Regulation of hepatic lipogenesis by the transcription factor XBP1.","volume":"320","author":"Lee","year":"2008","journal-title":"Science"},{"key":"2020071612403515100_B11","doi-asserted-by":"crossref","first-page":"9520","DOI":"10.1074\/jbc.M111421200","article-title":"Diminished hepatic response to fasting\/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c.","volume":"277","author":"Liang","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071612403515100_B12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cmet.2006.06.008","article-title":"Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis.","volume":"4","author":"Uyeda","year":"2006","journal-title":"Cell Metab"},{"key":"2020071612403515100_B13","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1507\/endocrj.K07E-110","article-title":"ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome.","volume":"55","author":"Iizuka","year":"2008","journal-title":"Endocr J"},{"key":"2020071612403515100_B14","doi-asserted-by":"crossref","first-page":"5107","DOI":"10.1073\/pnas.0730817100","article-title":"Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver.","volume":"100","author":"Kabashima","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612403515100_B15","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.bbrc.2009.09.109","article-title":"Replacing dietary glucose with fructose increases ChREBP activity and SREBP-1 protein in rat liver nucleus.","volume":"390","author":"Koo","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612403515100_B16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jhep.2011.07.019","article-title":"Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver.","volume":"56","author":"Dentin","year":"2012","journal-title":"J Hepatol"},{"key":"2020071612403515100_B17","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature10986","article-title":"A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism.","volume":"484","author":"Herman","year":"2012","journal-title":"Nature"},{"key":"2020071612403515100_B18","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.2337\/db06-0200","article-title":"Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob\/ob mice.","volume":"55","author":"Dentin","year":"2006","journal-title":"Diabetes"},{"key":"2020071612403515100_B19","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.2337\/diabetes.54.6.1846","article-title":"Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism.","volume":"54","author":"Watts","year":"2005","journal-title":"Diabetes"},{"key":"2020071612403515100_B20","doi-asserted-by":"crossref","first-page":"11288","DOI":"10.1073\/pnas.0812931106","article-title":"SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats.","volume":"106","author":"Erion","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612403515100_B21","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.cmet.2009.10.007","article-title":"Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein.","volume":"10","author":"Erion","year":"2009","journal-title":"Cell Metab"},{"key":"2020071612403515100_B22","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/o59-099","article-title":"A rapid method of total lipid extraction and purification.","volume":"37","author":"Bligh","year":"1959","journal-title":"Can J Biochem Physiol"},{"key":"2020071612403515100_B23","doi-asserted-by":"crossref","first-page":"E395","DOI":"10.1152\/ajpendo.00414.2001","article-title":"Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content.","volume":"282","author":"Neschen","year":"2002","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612403515100_B24","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease.","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"2020071612403515100_B25","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/(SICI)1096-9888(199606)31:6<639::AID-JMS336>3.0.CO;2-S","article-title":"Assay of the deuterium enrichment of water via acetylene.","volume":"31","author":"Previs","year":"1996","journal-title":"J Mass Spectrom"},{"key":"2020071612403515100_B26","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/(SICI)1096-9888(199701)32:1<81::AID-JMS454>3.0.CO;2-2","article-title":"Measuring lipogenesis and cholesterol synthesis in humans with deuterated water: use of simple gas chromatographic\/mass spectrometric techniques.","volume":"32","author":"Diraison","year":"1997","journal-title":"J Mass Spectrom"},{"key":"2020071612403515100_B27","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0026-0495(96)90152-3","article-title":"In vivo measurement of plasma cholesterol and fatty acid synthesis with deuterated water: determination of the average number of deuterium atoms incorporated.","volume":"45","author":"Diraison","year":"1996","journal-title":"Metabolism"},{"key":"2020071612403515100_B28","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.bbrc.2010.04.028","article-title":"Glucose-6-phosphate mediates activation of the carbohydrate responsive binding protein (ChREBP).","volume":"395","author":"Li","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612403515100_B29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1432-1033.1989.tb14537.x","article-title":"Stimulation of glucose phosphorylation by fructose in isolated rat hepatocytes.","volume":"179","author":"Van Schaftingen","year":"1989","journal-title":"Eur J Biochem"},{"key":"2020071612403515100_B30","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1097\/MOL.0b013e3282feea85","article-title":"Microsomal triglyceride transfer protein in plasma and cellular lipid metabolism.","volume":"19","author":"Hussain","year":"2008","journal-title":"Curr Opin Lipidol"},{"key":"2020071612403515100_B31","doi-asserted-by":"crossref","first-page":"28721","DOI":"10.1074\/jbc.M601576200","article-title":"ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver.","volume":"281","author":"Ma","year":"2006","journal-title":"J Biol Chem"},{"key":"2020071612403515100_B32","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1172\/JCI6576","article-title":"Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.","volume":"103","author":"Raabe","year":"1999","journal-title":"J Clin Invest"},{"key":"2020071612403515100_B33","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1194\/jlr.M300094-JLR200","article-title":"CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans.","volume":"44","author":"Chandler","year":"2003","journal-title":"J Lipid Res"},{"key":"2020071612403515100_B34","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1053\/jhep.2003.50309","article-title":"Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice.","volume":"38","author":"Lett\u00e9ron","year":"2003","journal-title":"Hepatology"},{"key":"2020071612403515100_B35","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1073\/pnas.0401516101","article-title":"Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.","volume":"101","author":"Iizuka","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612403515100_B36","doi-asserted-by":"crossref","first-page":"E358","DOI":"10.1152\/ajpendo.00027.2006","article-title":"Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob\/ob) mice.","volume":"291","author":"Iizuka","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612403515100_B37","doi-asserted-by":"crossref","first-page":"12121","DOI":"10.1073\/pnas.0812547106","article-title":"Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes.","volume":"106","author":"Samuel","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612403515100_B38","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1210\/endo-113-6-2181","article-title":"Diurnal rhythm for corticosterone in obese (ob\/ob) diabetes (db\/db) and gold-thioglucose-induced obesity in mice.","volume":"113","author":"Saito","year":"1983","journal-title":"Endocrinology"},{"key":"2020071612403515100_B39","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/S0140-6736(87)91419-X","article-title":"Study of hereditary fructose intolerance by use of 31P magnetic resonance spectroscopy.","volume":"2","author":"Oberhaensli","year":"1987","journal-title":"Lancet"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/154\/1\/36\/10385409\/endo0036.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/154\/1\/36\/10385409\/endo0036.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T21:29:28Z","timestamp":1594934968000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/154\/1\/36\/2423256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,1]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2012-1725","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,1]]}}}