{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:43:31Z","timestamp":1789987411129,"version":"4.0.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T00:00:00Z","timestamp":1546214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T00:00:00Z","timestamp":1546214400000},"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":[[2019,2]]},"abstract":"<jats:p>Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca<jats:sup>2+<\/jats:sup> release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll\u2010like receptor 4 (TLR4), which links to activation of nuclear factor\u2010\u03baB (NF\u2010\u03baB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF\u2010\u03baB, and promoter activity was inhibited by p65\/p50. Nested 0.5\u2010 and 1.0\u2010kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF\u2010\u03baB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF\u2010\u03baB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Stimulation of TLR4 by LPS activates NF\u2010\u03baB to down\u2010regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.<\/jats:p>","DOI":"10.1002\/hep.30228","type":"journal-article","created":{"date-parts":[[2018,8,24]],"date-time":"2018-08-24T01:29:46Z","timestamp":1535074186000},"page":"817-830","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":40,"title":["Effects of Endotoxin on Type 3 Inositol 1,4,5\u2010Trisphosphate Receptor in Human Cholangiocytes"],"prefix":"10.1097","volume":"69","author":[{"given":"Andressa","family":"Franca","sequence":"first","affiliation":[{"name":"Federal University of Minas Gerais (UFMG),Belo Horizonte,MG,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Carlos Melo Lima Filho","sequence":"additional","affiliation":[{"name":"Federal University of Minas Gerais (UFMG),Belo Horizonte,MG,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateus T.","family":"Guerra","sequence":"additional","affiliation":[{"name":"Section of Digestive Disease, Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jittima","family":"Weerachayaphorn","sequence":"additional","affiliation":[{"name":"Section of Digestive Disease, Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Physiology, Faculty of Science,Mahidol University,Bangkok,Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcone","family":"Loiola dos Santos","sequence":"additional","affiliation":[{"name":"Federal University of Minas Gerais (UFMG),Belo Horizonte,MG,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basile","family":"Njei","sequence":"additional","affiliation":[{"name":"Section of Digestive Disease, Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Robert","sequence":"additional","affiliation":[{"name":"Department of Pathology,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano","family":"Xavier Lima","sequence":"additional","affiliation":[{"name":"Federal University of Minas Gerais (UFMG),Belo Horizonte,MG,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Vieira Teixeira Vidigal","sequence":"additional","affiliation":[{"name":"Federal University of Minas Gerais (UFMG),Belo Horizonte,MG,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus M.","family":"Banales","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU), CIBERehd, Ikerbasque,San Sebastian,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshisundaram","family":"Ananthanarayanan","sequence":"additional","affiliation":[{"name":"Section of Digestive Disease, Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Fatima","family":"Leite","sequence":"additional","affiliation":[{"name":"Federal University of Minas Gerais (UFMG),Belo Horizonte,MG,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Nathanson","sequence":"additional","affiliation":[{"name":"Section of Digestive Disease, Department of Internal Medicine,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,12,31]]},"reference":[{"key":"hep30228-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.21480","article-title":"Sepsis\u2010induced cholestasis","volume":"45","year":"2007","journal-title":"Hepatology"},{"key":"hep30228-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/cc11381","article-title":"Clinical review: the liver in sepsis","volume":"16","year":"2012","journal-title":"Crit 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