Hepatic Sirt6 protects against cholestatic liver disease primarily via inhibiting bile acid synthesis rather than antioxidation or triggering mitochondrial biogenesis

Hepatic Sirt6 protects against cholestatic liver disease primarily via inhibiting bile acid synthesis rather than antioxidation or triggering mitochondrial biogenesis | 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 Research Article Hepatic Sirt6 protects against cholestatic liver disease primarily via inhibiting bile acid synthesis rather than antioxidation or triggering mitochondrial biogenesis Wen Zhang, Jiahui Wang, Luyao Yang, Yuyun Shao, Hongjun Peng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3932699/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 Cholestatic liver disease, caused by accumulation of hazardous bile acids in the liver, may result in cirrhosis, fibrosis, or liver failure. Activation of Sirt6 prevents cholestasis-associated pathological events such as oxidative stress and mitochondrial biogenesis disorders and inhibits bile acid synthesis to alleviate cholestatic liver injury. However, it is still uncertain which route is responsible for the therapeutic effect of Sirt6 in reducing cholestasis. For this reason, we administered liver-specific Sirt6 knockout mice with N-Acetylcysteine, Keap1-Nrf2-IN-1 or acadesine to remove oxidative stress and/or trigger mitochondrial biogenesis after cholestatic liver disease modeling, but these measures did not significantly improve cholestatic symptoms. Unlike the antioxidant or triggers of mitochondrial biogenesis, MDL801, a Sirt6 agonist suppressing CYP7A1 expression and down-regulating serum bile acid levels, exhibited favorable therapeutic effects. It suggests that inhibition of hepatic bile acid synthesis is the main pathway by which Sirt6 alleviates cholestatic liver disease. These findings provide a solid basis for the possible application of Sirt6 agonists in the treatment of cholestatic liver disease. sirtuin 6 cholestatic liver disease oxidative stress mitochondrial biogenesis bile acid synthesis Full Text Additional Declarations No competing interests reported. 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3932699","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271272912,"identity":"f5daa1c0-68ae-45fd-ae7b-81661312b36c","order_by":0,"name":"Wen Zhang","email":"","orcid":"","institution":"Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Zhang","suffix":""},{"id":271272913,"identity":"a0a152af-75ff-42d9-9d97-1108d366130e","order_by":1,"name":"Jiahui Wang","email":"","orcid":"","institution":"Nanjing Medical 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