{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:24:49Z","timestamp":1789615489237,"version":"build-2803163510"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T00:00:00Z","timestamp":1700524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81930015, 81730020, 82070592"],"award-info":[{"award-number":["81930015, 81730020, 82070592"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270610"],"award-info":[{"award-number":["82270610"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010097","name":"China Association for Science and Technology","doi-asserted-by":"publisher","award":["YESS20200034"],"award-info":[{"award-number":["YESS20200034"]}],"id":[{"id":"10.13039\/100010097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The \u201cgut-liver axis\u201d is critical for the control of hepatic lipid homeostasis, where the intestine affects the liver through multiple pathways, such as nutrient uptake, gastrointestinal hormone release, and gut microbiota homeostasis. Whether intestine-originated exosomes mediate the gut\u2019s influence on liver steatosis remains unknown. Here, we aimed to determine whether intestinal epithelium-derived exosomes (intExos) contribute to the regulation of hepatic lipid metabolism. We found that mouse intExos could be taken up by hepatic cells. Mice fed high-fat diet (HFD) received intExos showed strong resistance to liver steatosis. MicroRNA sequencing of intExos indicated the correlation between miR-21a-5p\/miR-145a-5p and hepatic lipid metabolism. Both liver overexpression of miR-21a-5p and intExos containing miR-21a-5p alleviated hepatic steatosis in mice fed with HFD. Mechanistically, miR-21a-5p suppressed the expression of Ccl1 (C-C motif chemokine ligand 1) in macrophages, as well as lipid transport genes Cd36 (cluster of differentiation 36) and Fabp7 (fatty acid binding protein 7) in hepatocytes. Liver-specific inhibition of miR-145a-5p significantly reduced hepatic lipid accumulation in mice fed with HFD through negatively regulating the expression of Btg1 (BTG anti-proliferation factor 1), leading to an increase of stearoyl-CoA desaturase-1 and lipogenesis. Our study demonstrates that intExos regulate hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD) progression via miR-21a-5p and miR-145a-5p pathways, providing novel mediators for the gut-liver crosstalk and potential targets for regulating hepatic lipid metabolism.<\/jats:p>","DOI":"10.1093\/lifemeta\/load044","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T18:22:13Z","timestamp":1700590933000},"source":"Crossref","is-referenced-by-count":16,"title":["Regulation of hepatic lipid metabolism by intestine epithelium-derived exosomes"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4642-9905","authenticated-orcid":false,"given":"Tiange","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W","family":"Mulholland","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan Medical Center , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University , Beijing 100191 , China"},{"name":"Department of Surgery, University of Michigan Medical Center , Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,11,21]]},"reference":[{"key":"2024011900015541600_CIT0001","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cld.2013.09.018","article-title":"Obesity-associated nonalcoholic fatty liver disease","volume":"18","author":"Yilmaz","year":"2014","journal-title":"Clin Liver Dis"},{"key":"2024011900015541600_CIT0002","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut-liver axis in liver disease: pathophysiological basis for therapy","volume":"72","author":"Albillos","year":"2020","journal-title":"J Hepatol"},{"key":"2024011900015541600_CIT0003","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3390\/microorganisms8040527","article-title":"Role of gut microbiota in neuroendocrine regulation of carbohydrate and lipid metabolism via the microbiota-gut-brain-liver axis","volume":"8","author":"Wang","year":"2020","journal-title":"Microorganisms"},{"key":"2024011900015541600_CIT0004","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41575-020-0269-9","article-title":"Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders","volume":"17","author":"Aron-Wisnewsky","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2024011900015541600_CIT0005","doi-asserted-by":"crossref","first-page":"700","DOI":"10.3389\/fgene.2020.00700","article-title":"Characterizing extracellular vesicles and their diverse RNA contents","volume":"11","author":"Veziroglu","year":"2020","journal-title":"Front Genet"},{"key":"2024011900015541600_CIT0006","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Th\u00e9ry","year":"2018","journal-title":"J Extracell Vesicles"},{"key":"2024011900015541600_CIT0007","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1136\/gut.52.12.1690","article-title":"Intestinal epithelial exosomes carry MHC class II\/peptides able to inform the immune system in mice","volume":"52","author":"Van Niel","year":"2003","journal-title":"Gut"},{"key":"2024011900015541600_CIT0008","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1016\/j.cmet.2021.08.006","article-title":"Exosomes as mediators of intercellular crosstalk in metabolism","volume":"33","author":"Isaac","year":"2021","journal-title":"Cell Metab"},{"key":"2024011900015541600_CIT0009","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41580-020-0251-y","article-title":"RNA delivery by extracellular vesicles in mammalian cells and its applications","volume":"21","author":"O\u2019Brien","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2024011900015541600_CIT0010","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12964-020-00581-2","article-title":"The crosstalk: exosomes and lipid metabolism","volume":"18","author":"Wang","year":"2020","journal-title":"Cell Commun Signal"},{"key":"2024011900015541600_CIT0011","doi-asserted-by":"crossref","first-page":"e0217546","DOI":"10.1371\/journal.pone.0217546","article-title":"Circulating exosomes deliver free fatty acids from the bloodstream to cardiac cells: possible role of CD36","volume":"14","author":"Garcia","year":"2019","journal-title":"PLoS One"},{"key":"2024011900015541600_CIT0012","doi-asserted-by":"crossref","first-page":"669429","DOI":"10.3389\/fphys.2021.669429","article-title":"Multifaceted roles of adipose tissue-derived exosomes in physiological and pathological conditions","volume":"12","author":"Liu","year":"2021","journal-title":"Front Physiol"},{"key":"2024011900015541600_CIT0013","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.cmet.2017.03.012","article-title":"Brown fat-derived exosomes: small vesicles with big impact","volume":"25","author":"Chen","year":"2017","journal-title":"Cell Metab"},{"key":"2024011900015541600_CIT0014","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nature21365","article-title":"Adipose-derived circulating miRNAs regulate gene expression in other tissues","volume":"542","author":"Thomou","year":"2017","journal-title":"Nature"},{"key":"2024011900015541600_CIT0015","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3390\/cells12010169","article-title":"Exosomes from short-term high-fat or high-sucrose fed mice induce hepatic steatosis through different pathways","volume":"12","author":"Casta\u00f1o","year":"2022","journal-title":"Cells"},{"key":"2024011900015541600_CIT0016","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.4049\/jimmunol.1203170","article-title":"Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells","volume":"190","author":"Deng","year":"2013","journal-title":"J Immunol"},{"key":"2024011900015541600_CIT0017","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1002\/mnfr.201200182","article-title":"Lycopene inhibits hepatic steatosis via microRNA-21-induced downregulation of fatty acid-binding protein 7 in mice fed a high-fat diet","volume":"56","author":"Ahn","year":"2012","journal-title":"Mol Nutr Food Res"},{"key":"2024011900015541600_CIT0018","doi-asserted-by":"crossref","first-page":"e47903","DOI":"10.15252\/embr.201947903","article-title":"Inter-organ communication: a gatekeeper for metabolic health","volume":"20","author":"Castillo-Armengol","year":"2019","journal-title":"EMBO Rep"},{"key":"2024011900015541600_CIT0019","doi-asserted-by":"crossref","first-page":"608680","DOI":"10.3389\/fimmu.2021.608680","article-title":"Adipose extracellular vesicles in intercellular and inter-organ crosstalk in metabolic health and diseases","volume":"12","author":"Huang","year":"2021","journal-title":"Front Immunol"},{"key":"2024011900015541600_CIT0020","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.cell.2017.08.035","article-title":"Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity","volume":"171","author":"Ying","year":"2017","journal-title":"Cell"},{"key":"2024011900015541600_CIT0021","doi-asserted-by":"crossref","first-page":"11966","DOI":"10.1038\/s41598-021-91583-8","article-title":"Improvement of hyperlipidemia by aerobic exercise in mice through a regulatory effect of miR-21a-5p on its target genes","volume":"11","author":"Zhao","year":"2021","journal-title":"Sci Rep"},{"key":"2024011900015541600_CIT0022","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3892\/ijmm.2015.2076","article-title":"miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR","volume":"35","author":"Sun","year":"2015","journal-title":"Int J Mol Med"},{"key":"2024011900015541600_CIT0023","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.cca.2013.05.021","article-title":"Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver","volume":"424","author":"Yamada","year":"2013","journal-title":"Clin Chim Acta"},{"key":"2024011900015541600_CIT0024","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1136\/gutjnl-2015-310822","article-title":"Stress-activated miR-21\/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption","volume":"65","author":"Calo","year":"2016","journal-title":"Gut"},{"key":"2024011900015541600_CIT0025","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1136\/gutjnl-2014-308430","article-title":"MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway","volume":"65","author":"Wu","year":"2016","journal-title":"Gut"},{"key":"2024011900015541600_CIT0026","doi-asserted-by":"crossref","first-page":"e2748","DOI":"10.1038\/cddis.2017.172","article-title":"miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice","volume":"8","author":"Rodrigues","year":"2017","journal-title":"Cell Death Dis"},{"key":"2024011900015541600_CIT0027","first-page":"2201","article-title":"Role and mechanisms of action of microRNA\u201121 as regards the regulation of the WNT\/\u03b2\u2011catenin signaling pathway in the pathogenesis of non\u2011alcoholic fatty liver disease","volume":"44","author":"Wang","year":"2019","journal-title":"Int J Mol Med"},{"key":"2024011900015541600_CIT0028","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1136\/gutjnl-2014-308883","article-title":"Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPAR\u03b1 expression","volume":"65","author":"Loyer","year":"2016","journal-title":"Gut"},{"key":"2024011900015541600_CIT0029","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1002\/hep.24764","article-title":"Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice","volume":"55","author":"Heymann","year":"2012","journal-title":"Hepatology"},{"key":"2024011900015541600_CIT0030","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1080\/13813455.2020.1762657","article-title":"Can miR-145-5p be used as a marker in diabetic patients","volume":"128","author":"Shahrokhi","year":"2022","journal-title":"Arch Physiol Biochem"},{"key":"2024011900015541600_CIT0031","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/jmcb\/mjz015","article-title":"miR-145 improves metabolic inflammatory disease through multiple pathways","volume":"12","author":"He","year":"2020","journal-title":"J Mol Cell Biol"},{"key":"2024011900015541600_CIT0032","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.bbrc.2016.05.057","article-title":"Methylation of miR-145a-5p promoter mediates adipocytes differentiation","volume":"475","author":"Du","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"key":"2024011900015541600_CIT0033","doi-asserted-by":"crossref","first-page":"13787","DOI":"10.3390\/ijms232213787","article-title":"Microbiota-derived extracellular vesicles detected in human blood from healthy donors","volume":"23","author":"Schaack","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2024011900015541600_CIT0034","doi-asserted-by":"crossref","first-page":"893617","DOI":"10.3389\/fimmu.2022.893617","article-title":"The potential role of gut microbial-derived exosomes in metabolic-associated fatty liver disease: implications for treatment","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Immunol"},{"key":"2024011900015541600_CIT0035","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1111\/bph.15193","article-title":"The ARRIVE guidelines 20: updated guidelines for reporting animal research","volume":"177","author":"Percie du Sert","year":"2020","journal-title":"Br J Pharmacol"},{"key":"2024011900015541600_CIT0036","doi-asserted-by":"crossref","first-page":"G123","DOI":"10.1152\/ajpgi.00056.2018","article-title":"LGR4 protects hepatocytes from injury in mouse","volume":"316","author":"Li","year":"2019","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2024011900015541600_CIT0037","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1007\/s12325-017-0556-1","article-title":"NAFLD as a sexual dimorphic disease: role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk","volume":"34","author":"Ballestri","year":"2017","journal-title":"Adv Ther"},{"key":"2024011900015541600_CIT0038","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s12033-019-00163-9","article-title":"A high efficient method to isolate exosomes from small intestinal epithelium","volume":"61","author":"Xia","year":"2019","journal-title":"Mol Biotechnol"},{"key":"2024011900015541600_CIT0039","doi-asserted-by":"crossref","first-page":"13163","DOI":"10.1073\/pnas.1411571111","article-title":"Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPAR\u03b3 signaling pathway","volume":"111","author":"Li","year":"2014","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Life Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/lifemeta\/advance-article-pdf\/doi\/10.1093\/lifemeta\/load044\/53668443\/load044.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/lifemeta\/article-pdf\/2\/6\/load044\/56218789\/load044.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/lifemeta\/article-pdf\/2\/6\/load044\/56218789\/load044.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T19:02:13Z","timestamp":1705604533000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/lifemeta\/article\/doi\/10.1093\/lifemeta\/load044\/7439699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,21]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/lifemeta\/load044","relation":{},"ISSN":["2755-0230"],"issn-type":[{"value":"2755-0230","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12,1]]},"published":{"date-parts":[[2023,11,21]]},"article-number":"load044"}}