{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:51:53Z","timestamp":1790707913119,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T00:00:00Z","timestamp":1520380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science","award":["17K00850"],"award-info":[{"award-number":["17K00850"]}]},{"name":"Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science","award":["26500005,"],"award-info":[{"award-number":["26500005,"]}]},{"name":"Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science","award":["17K19902"],"award-info":[{"award-number":["17K19902"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp mRNA and protein levels of Shp\u2212\/\u2212 mice were similar to those of wild-types; however, those of Chrebp\u2212\/\u2212Shp\u2212\/\u2212 and Chrebp\u2212\/\u2212 mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp\u2212\/\u2212 mice were similar to wild-types but were much lower in Chrebp\u2212\/\u2212 and Chrebp\u2212\/\u2212Shp\u2212\/\u2212 mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other.<\/jats:p>","DOI":"10.3390\/nu10030321","type":"journal-article","created":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T12:55:23Z","timestamp":1520427323000},"page":"321","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-9206","authenticated-orcid":false,"given":"Hiroyuki","family":"Niwa","sequence":"first","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-6238","authenticated-orcid":false,"given":"Katsumi","family":"Iizuka","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"},{"name":"Gifu University Hospital Center for Nutritional Support and Infection Control, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiro","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wudelehu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Takao","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Horikawa","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4995","DOI":"10.3390\/nu7064995","article-title":"Hepatic Steatosis as a Marker of Metabolic Dysfunction","volume":"7","author":"Fabbrini","year":"2015","journal-title":"Nutrients"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/hep.23280","article-title":"Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications","volume":"51","author":"Fabbrini","year":"2010","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.bcp.2012.09.019","article-title":"High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload","volume":"85","author":"Agius","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1210\/jc.2004-1983","article-title":"Dietary fat content modifies liver fat in overweight nondiabetic subjects","volume":"90","author":"Westerbacka","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2862173","DOI":"10.1155\/2016\/2862173","article-title":"The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background","volume":"2016","author":"Yu","year":"2016","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI23621","article-title":"Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1172\/JCI200422422","article-title":"Molecular mediators of hepatic steatosis and liver injury","volume":"114","author":"Browning","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/MOL.0b013e32836139df","article-title":"Microsomal transfer protein inhibition in humans","volume":"24","author":"Cuchel","year":"2013","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2217\/clp.11.21","article-title":"Regulation of microsomal triglyceride transfer protein","volume":"6","author":"Hussain","year":"2011","journal-title":"Clin. Lipidol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.bbadis.2010.10.006","article-title":"Role of nuclear receptor SHP in metabolism and cancer","volume":"1812","author":"Zhang","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1073\/pnas.98.2.575","article-title":"Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects","volume":"98","author":"Nishigori","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E271","DOI":"10.1002\/humu.20865","article-title":"Mutations in the small heterodimer partner gene increase morbidity risk in Japanese type 2 diabetes patients","volume":"29","author":"Enya","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1128\/MCB.20.1.187-195.2000","article-title":"The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: Two mechanisms for repression","volume":"20","author":"Lee","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S1097-2765(00)00051-4","article-title":"A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis","volume":"6","author":"Goodwin","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1194\/jlr.M016048","article-title":"Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner","volume":"52","author":"Park","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/hep.21632","article-title":"Molecular characterization of the role of orphan receptor small heterodimerpartner in development of fatty liver","volume":"46","author":"Huang","year":"2007","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"29138","DOI":"10.1016\/S0021-9258(19)62022-3","article-title":"Cloning and regulation of hamster microsomal triglyceride transfer protein. The regulation is independent from that of other hepatic and intestinal proteins which participate in the transport of fatty acids and triglycerides","volume":"269","author":"Lin","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jnutbio.2016.09.010","article-title":"High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation","volume":"39","author":"Mock","year":"2017","journal-title":"J. Nutr. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.bbrc.2015.04.092","article-title":"Fat and carbohydrate in western diet contribute differently to hepatic lipid accumulation","volume":"461","author":"Wu","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","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":"ref_21","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.bbadis.2016.11.029","article-title":"The transcription factor carbohydrate-response element-binding protein (ChREBP): A possible link between metabolic disease and cancer","volume":"1863","author":"Iizuka","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cmet.2017.07.004","article-title":"Sweet Sixteenth for ChREBP: Established Roles and Future Goals","volume":"26","author":"Guilmeau","year":"2017","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.tem.2016.06.005","article-title":"The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis","volume":"27","author":"Herman","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.bbadis.2011.03.015","article-title":"Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors","volume":"1812","author":"Poupeau","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1128\/MCB.01004-12","article-title":"Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes","volume":"33","author":"Caron","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23944","DOI":"10.1038\/srep23944","article-title":"Identification of HNF-4\u03b1 as a key transcription factor to promote ChREBP expression in response to glucose","volume":"6","author":"Meng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7629","DOI":"10.1038\/ncomms8629","article-title":"Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells","volume":"6","author":"Trabelsi","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1096\/fj.08-126631","article-title":"cAMP opposes the glucose-mediated induction of the L-PK gene by preventing the recruitment of a complex containing ChREBP, HNF4alpha, and CBP","volume":"23","author":"Burke","year":"2009","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"McFerrin, L.G., and Atchley, W.R. (2012). A novel N-terminal domain may dictate the glucose response of Mondo proteins. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034803"},{"key":"ref_30","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":"ref_31","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.bbrc.2008.06.101","article-title":"Regulation of lipogenesis via BHLHB2\/DEC1 and ChREBP feedback looping","volume":"374","author":"Iizuka","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1016\/j.febslet.2009.07.053","article-title":"Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes","volume":"583","author":"Iizuka","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.5650\/jos.ess16020","article-title":"Recent Advances in Analytical Methods on Lipoprotein Subclasses: Caluculation of Particle Numbers from Lipid Levels by Gel Permeation HPLC Using \u201cSpherical Particle Model\u201d","volume":"65","author":"Okazaki","year":"2016","journal-title":"J. Oleo Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"45685","DOI":"10.1074\/jbc.M404255200","article-title":"Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceridetransfer protein gene expression mediated by hepatocyte nuclear factor-4","volume":"279","author":"Hirokane","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Jeong, Y.S., Kim, D., Lee, Y.S., Kim, H.J., Han, J.Y., Im, S.S., Chong, H.K., Kwon, J.K., Cho, Y.H., and Kim, W.K. (2011). Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucose-regulated gene expression. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022544"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1210\/en.2014-1666","article-title":"Genome-Wide Analysis of ChREBP Binding Sites on Male Mouse Liver and White Adipose Chromatin","volume":"156","author":"Poungvarin","year":"2015","journal-title":"Endocrinology"},{"key":"ref_38","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":"ref_39","doi-asserted-by":"crossref","unstructured":"Iizuka, K. (2017). The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism. Nutrients, 9.","DOI":"10.3390\/nu9020181"},{"key":"ref_40","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":"ref_41","doi-asserted-by":"crossref","first-page":"e96703","DOI":"10.1172\/jci.insight.96703","article-title":"Intestinal, but not hepatic, ChREBP is required for fructose tolerance","volume":"2","author":"Kim","year":"2017","journal-title":"JCI Insight"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1194\/jlr.M081836","article-title":"Interplay between ChREBP and SREBP-1c Coordinates Postprandial Glycolysis and Lipogenesis in Livers of Mice","volume":"59","author":"Linden","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1074\/jbc.M706540200","article-title":"Carbohydrate-response element-binding protein deletion alters substrate utilization producing an energy-deficient liver","volume":"283","author":"Burgess","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/1479-5876-12-186","article-title":"Progression of diet induced nonalcoholic steatohepatitis is accompanied by increased expression of kruppel-like-factor 10 in mice","volume":"12","author":"Kim","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0303-7207(01)00475-0","article-title":"The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase","volume":"176","author":"Kassam","year":"2001","journal-title":"Mol. Cell. Endocrinol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/3\/321\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:53Z","timestamp":1760194673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/3\/321"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,7]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["nu10030321"],"URL":"https:\/\/doi.org\/10.3390\/nu10030321","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,7]]}}}