Cholangiocyte RAGE drives the ductular reaction which provides biliary drainage but fuels liver injury

Cholangiocyte RAGE drives the ductular reaction which provides biliary drainage but fuels liver injury | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cholangiocyte RAGE drives the ductular reaction which provides biliary drainage but fuels liver injury Nachiket Vartak, Amruta Damle-Vartak, Simone Joers, Georgia Guenther, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4337701/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Ductular reactions inevitably co-occur with liver tissue injury along with inflammation, cholestasis, and fibrosis. However, it remains unknown whether they represent an adaptive response facilitating bile drainage, or if they exacerbate dysfunction. By using a reporter mouse with cholangiocyte-specific deletion of the pattern recognition receptor RAGE, specific effects of the DR could be differentiated from the consequences of the cytotoxicity of the CDE-diet. While CDE-diet induced hepatoxicity triggers the DR via RAGE-dependent DAMP-sensing on cholangiocytes, it does not itself lead to loss of liver function. Instead, the presence of DR causes downregulation of basolateral bile acid transporters. Thus, although the DR forms a contiguous network capable of draining bile, it remains unutilized due to interrupted bile acid transport from blood to hepatocytes. The de-differentiating influence of the DR on hepatocytes thereby results in cholestasis and eventual fibrosis, that are more insidious to liver function than its initial cytotoxic trigger. Biological sciences/Physiology Biological sciences/Systems biology/Multicellular systems Biological sciences/Cell biology/Mechanisms of disease liver regeneration cholangiocytes receptor for advanced glycation end products (RAGE) ductular reaction (DR) bile ducts intrahepatic cholestasis 3D imaging live imaging Full Text Additional Declarations There is NO Competing Interest. Supplementary Files M1ImagingofIntrahepaticbs01.mp4 3D imaging of the intrahepatic biliary system M2CanaliculaConnectivity01.mp4 Canalicular interconnectivity in homeostasis and CDE-diet injury M3PhotoactivationCMNB01.mp4 Intravital photoactivation of CMNB-caged fluorescein M4CLFTransport01.mp4 Intravital imaging of CLF Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4337701","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":298078356,"identity":"31be62ae-83e6-4f87-93d2-5a343f2c19a7","order_by":0,"name":"Nachiket Vartak","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYNCCAzYJbAyMDUCWBEQAzMYNgNIH0pC1MBOl5XACkgABLQbHzz5/8OPM+Tw+9ubWDT9+WeTJO/AffPBzBx4tZ9ING3tu3C5m4znYdrO3T6LY8AAzs2HvGdxaJBvSGBt4PtxObJNIbLvB2yORuLGBmU2asQ2Plv5njI1/PpwDa7n5F6KF/Tc+LfwSaYzNPDcOgLXc5vkhkTifgZmNGb+WZ4yzZc4kg/1yW7ZBInEDM7OxZC8eLWz8aQwf3xyzy5Nvb392882fusT57Y0PP/zEowUVgNxjcJhY1RDwh4FBvoE0LaNgFIyCUTD8AQC701ofrwpUZQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8813-4799","institution":"Leibniz Research Centre for Working Environment and Human Factors","correspondingAuthor":true,"prefix":"","firstName":"Nachiket","middleName":"","lastName":"Vartak","suffix":""},{"id":298078358,"identity":"78e7c1da-f85b-4b72-a9c8-c2971420bba9","order_by":1,"name":"Amruta Damle-Vartak","email":"","orcid":"","institution":"German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance","correspondingAuthor":false,"prefix":"","firstName":"Amruta","middleName":"","lastName":"Damle-Vartak","suffix":""},{"id":298078360,"identity":"805c5eb3-e654-44f5-b80c-1ed5a23d507e","order_by":2,"name":"Simone Joers","email":"","orcid":"","institution":"University Medical Center, Technical University of Munich","correspondingAuthor":false,"prefix":"","firstName":"Simone","middleName":"","lastName":"Joers","suffix":""},{"id":298078361,"identity":"6838f096-2bae-48a8-bd26-3bd92abeeab8","order_by":3,"name":"Georgia Guenther","email":"","orcid":"","institution":"Leibniz Research Centre for Working Environment and Human Factors","correspondingAuthor":false,"prefix":"","firstName":"Georgia","middleName":"","lastName":"Guenther","suffix":""},{"id":298078362,"identity":"e6aa022c-8d95-4148-b6e6-a365cab83534","order_by":4,"name":"Macrina Lam","email":"","orcid":"","institution":"Univ. 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