Taurolithocholic acid alleviates hepatic glycolipid dysregulation in low birth weight piglets by activating HNF4α and FXR

Taurolithocholic acid alleviates hepatic glycolipid dysregulation in low birth weight piglets by activating HNF4α and FXR | 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 Taurolithocholic acid alleviates hepatic glycolipid dysregulation in low birth weight piglets by activating HNF4α and FXR Tianle Gao, Hairong Liang, Meizheng Li, Rui Zhou, Li Wang, Ran Li, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8842634/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Low-birth-weight (LBW) piglets often exhibit glycolipid metabolic disorders at birth, which severely impairs their postnatal growth and survival. Bile acids (BAs) act as signaling molecules that participate in the regulation of glycolipid metabolism; however, whether the hepatic metabolic abnormalities observed in LBW piglets are associated with altered BA metabolism remains largely unclear. Thus, using naturally occurring LBW fetal piglets, neonatal piglets, and hepatic cell lines as experimental models, the present study aimed to elucidate the association between bile acid homeostasis and hepatic glycolipid metabolism, and to investigate the underlying molecular mechanisms involved, through integrated analyses of bile acid-targeted metabolomics, 16S rRNA gene sequencing, and molecular docking. Result Compared with normal-birth-weight (NBW) fetal pigs, LBW exhibited a marked reduction in hepatic glycogen storage accompanied by excessive lipid accumulation. As key nuclear receptors governing glycolipid metabolism, farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) were significantly down-regulated in the liver of LBW fetal piglets at both the transcriptional and protein levels, which was coupled with impaired glycogen synthetic capacity and lipolytic capacity in these fetal pigs. Targeted bile acid metabolomic analysis revealed a profound alteration in the hepatic bile acid profile of LBW fetal pigs, characterized by an increased proportion of secondary bile acids. Notably, the hepatic level of taurolithocholic acid (TLCA) was markedly decreased in LBW fetal piglets. Further analyses demonstrated that critical processes of bile acid metabolism, including synthesis, transport, detoxification and conjugation, were impaired in LBW fetal piglets, along with disrupted endogenous TLCA biosynthesis. Mechanistically, molecular docking results suggested that TLCA might act as a potential agonist of FXR and HNF4α. In vitro assays confirmed that TLCA modulates hepatic glycolipid metabolism by activating FXR and HNF4α. More importantly, in vivo experiments indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets. Conclusions These findings reveal crosstalk between hepatic glucose-lipid and bile acid metabolism via HNF4α and FXR, providing potential nutritional strategies to improve liver health in LBW piglets and a theoretical basis for using BAs as feed additives in pig production. Bile acid FXR HNF4α Low birth weight piglet TLCA Full Text Additional Declarations No competing interests reported. Supplementary Files JASBSupplementaryfile.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Apr, 2026 Reviews received at journal 07 Apr, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviews received at journal 11 Mar, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviewers invited by journal 25 Feb, 2026 Editor assigned by journal 14 Feb, 2026 Submission checks completed at journal 14 Feb, 2026 First submitted to journal 10 Feb, 2026 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. 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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-8842634","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597539203,"identity":"dadb6340-a4cc-46e0-bf8f-f5bfdb276e8b","order_by":0,"name":"Tianle Gao","email":"","orcid":"","institution":"Sichuan Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Tianle","middleName":"","lastName":"Gao","suffix":""},{"id":597539204,"identity":"9609ebcf-0f95-4424-b1a9-7918bb61c10a","order_by":1,"name":"Hairong Liang","email":"","orcid":"","institution":"Sichuan Agricultural 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Biotechnology","twitterHandle":"@animalplantsci","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bile acid, FXR, HNF4α, Low birth weight, piglet, TLCA","lastPublishedDoi":"10.21203/rs.3.rs-8842634/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8842634/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLow-birth-weight (LBW) piglets often exhibit glycolipid metabolic disorders at birth, which severely impairs their postnatal growth and survival. Bile acids (BAs) act as signaling molecules that participate in the regulation of glycolipid metabolism; however, whether the hepatic metabolic abnormalities observed in LBW piglets are associated with altered BA metabolism remains largely unclear. Thus, using naturally occurring LBW fetal piglets, neonatal piglets, and hepatic cell lines as experimental models, the present study aimed to elucidate the association between bile acid homeostasis and hepatic glycolipid metabolism, and to investigate the underlying molecular mechanisms involved, through integrated analyses of bile acid-targeted metabolomics, 16S rRNA gene sequencing, and molecular docking.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eCompared with normal-birth-weight (NBW) fetal pigs, LBW exhibited a marked reduction in hepatic glycogen storage accompanied by excessive lipid accumulation. As key nuclear receptors governing glycolipid metabolism, farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) were significantly down-regulated in the liver of LBW fetal piglets at both the transcriptional and protein levels, which was coupled with impaired glycogen synthetic capacity and lipolytic capacity in these fetal pigs. Targeted bile acid metabolomic analysis revealed a profound alteration in the hepatic bile acid profile of LBW fetal pigs, characterized by an increased proportion of secondary bile acids. Notably, the hepatic level of taurolithocholic acid (TLCA) was markedly decreased in LBW fetal piglets. Further analyses demonstrated that critical processes of bile acid metabolism, including synthesis, transport, detoxification and conjugation, were impaired in LBW fetal piglets, along with disrupted endogenous TLCA biosynthesis. Mechanistically, molecular docking results suggested that TLCA might act as a potential agonist of FXR and HNF4α. In vitro assays confirmed that TLCA modulates hepatic glycolipid metabolism by activating FXR and HNF4α. More importantly, in vivo experiments indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThese findings reveal crosstalk between hepatic glucose-lipid and bile acid metabolism via HNF4α and FXR, providing potential nutritional strategies to improve liver health in LBW piglets and a theoretical basis for using BAs as feed additives in pig production.\u003c/p\u003e","manuscriptTitle":"Taurolithocholic acid alleviates hepatic glycolipid dysregulation in low birth weight piglets by activating HNF4α and FXR","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 10:14:16","doi":"10.21203/rs.3.rs-8842634/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-10T10:24:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-07T05:18:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"191382142556765222638263867849175398888","date":"2026-03-26T21:29:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-11T16:37:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"157655477445061707578635595803687706667","date":"2026-02-25T10:16:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-25T08:57:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-14T05:04:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-14T05:04:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Animal Science and Biotechnology","date":"2026-02-10T14:12:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-animal-science-and-biotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jasb","sideBox":"Learn more about [Journal of Animal Science and Biotechnology](http://jasbsci.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jasb/default.aspx","title":"Journal of Animal Science and Biotechnology","twitterHandle":"@animalplantsci","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f1ec45c1-4391-4c18-b14c-f01242fba041","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T00:53:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 10:14:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8842634","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8842634","identity":"rs-8842634","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}