Hepatic ACE2 Shapes Liver–Islet Communication through Exosomal miR-30c-5p to Preserve β-Cell Function

Hepatic ACE2 Shapes Liver–Islet Communication through Exosomal miR-30c-5p to Preserve β-Cell Function | 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 ACE2 Shapes Liver–Islet Communication through Exosomal miR-30c-5p to Preserve β-Cell Function Yuanyuan Gao, Qi Chen, Zhuoying Wu, Songtao Yang, Ying Wang, Li yuan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8110334/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 Background : Progressive dysfunction of pancreatic β-cells is a hallmark of diabetes development. The liver–islet axis is critical for maintaining β-cell function, where hepatocyte-derived exosomes (HExos) transport specific miRNAs and proteins to regulate β-cell gene expression and survival. Angiotensin-converting enzyme 2 (ACE2) is known to modulate systemic metabolic homeostasis and may influence β-cell status by altering exosomal secretion and cargo composition. Methods : We isolated HExos from wild-type (WT-HExos) and ACE2 knockout (ACE2KO-HExos) mice, and assessed their effects in a high-fat diet (HFD)-induced metabolic stress mouse model and palmitate-treated MIN6 cells. Exosomal miRNA profiles were analyzed via high-throughput sequencing, followed by molecular and functional validation of key targets and pathways. Adeno-associated virus-mediated ACE2 or miR-30c-5p overexpression in primary hepatocytes enabled functional rescue experiments in ACE2KO mice. Results : WT-HExos enhancing insulin secretion, preserving β-cell mass, improving glucose tolerance and insulin sensitivity, and mitigating hepatic steatosis and visceral adiposity. In contrast, ACE2KO-HExos exhibited markedly diminished efficacy. Sequencing revealed significant downregulation of miR-30c-5p in ACE2KO-HExos. Mechanistically, miR-30c-5p targets Mitogen-Activated Protein Kinase Kinase Kinase 20 (Map3k20) to inhibit c-Jun N-terminal kinase (JNK) pathway activation, thereby blocking Bax-mediated mitochondrial apoptosis and protecting β-cell function and survival. Exosomes derived from ACE2- or miR-30c-5p-overexpressing hepatocytes restored metabolic and β-cell defects in ACE2KO mice under HFD challenge. Conclusion : This study uncovers hepatic ACE2 as a pivotal regulator of liver–islet inter-organ communication via miR-30c-5p–enriched exosomes. The miR-30c-5p–Map3k20–JNK axis suppresses β-cell mitochondrial apoptosis, preserving β-cell function and offering a promising therapeutic target for diabetes through engineered exosome interventions. Exosomes Liver–islet axis ACE2 miRNA signaling β-cell survival Full Text Supplementary Files Originalwesternblotimage.pdf Supplementarymaterial.pdf 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-8110334","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":553783890,"identity":"285b3ee6-0801-43f0-885a-c45d070592a0","order_by":0,"name":"Yuanyuan Gao","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yuanyuan","middleName":"","lastName":"Gao","suffix":""},{"id":553783891,"identity":"717765ed-db69-4d5c-aafe-82d24dbc3dad","order_by":1,"name":"Qi Chen","email":"","orcid":"","institution":"Huazhong University of Science 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survival","lastPublishedDoi":"10.21203/rs.3.rs-8110334/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8110334/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Progressive dysfunction of pancreatic β-cells is a hallmark of diabetes development. The liver–islet axis is critical for maintaining β-cell function, where hepatocyte-derived exosomes (HExos) transport specific miRNAs and proteins to regulate β-cell gene expression and survival. Angiotensin-converting enzyme 2 (ACE2) is known to modulate systemic metabolic homeostasis and may influence β-cell status by altering exosomal secretion and cargo composition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We isolated HExos from wild-type (WT-HExos) and ACE2 knockout (ACE2KO-HExos) mice, and assessed their effects in a high-fat diet (HFD)-induced metabolic stress mouse model and palmitate-treated MIN6 cells. Exosomal miRNA profiles were analyzed via high-throughput sequencing, followed by molecular and functional validation of key targets and pathways. Adeno-associated virus-mediated ACE2 or miR-30c-5p overexpression in primary hepatocytes enabled functional rescue experiments in ACE2KO mice.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: WT-HExos enhancing insulin secretion, preserving β-cell mass, improving glucose tolerance and insulin sensitivity, and mitigating hepatic steatosis and visceral adiposity. In contrast, ACE2KO-HExos exhibited markedly diminished efficacy. Sequencing revealed significant downregulation of miR-30c-5p in ACE2KO-HExos. Mechanistically, miR-30c-5p targets Mitogen-Activated Protein Kinase Kinase Kinase 20 (Map3k20) to inhibit c-Jun N-terminal kinase (JNK) pathway activation, thereby blocking Bax-mediated mitochondrial apoptosis and protecting β-cell function and survival. Exosomes derived from ACE2- or miR-30c-5p-overexpressing hepatocytes restored metabolic and β-cell defects in ACE2KO mice under HFD challenge.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: This study uncovers hepatic ACE2 as a pivotal regulator of liver–islet inter-organ communication via miR-30c-5p–enriched exosomes. The miR-30c-5p–Map3k20–JNK axis suppresses β-cell mitochondrial apoptosis, preserving β-cell function and offering a promising therapeutic target for diabetes through engineered exosome interventions.\u003c/p\u003e","manuscriptTitle":"Hepatic ACE2 Shapes Liver–Islet Communication through Exosomal miR-30c-5p to Preserve β-Cell Function","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-03 08:48:00","doi":"10.21203/rs.3.rs-8110334/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"625df546-cb61-40f3-8026-7ad78e3e49b1","owner":[],"postedDate":"December 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-12T23:32:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-03 08:48:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8110334","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8110334","identity":"rs-8110334","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}