{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:39:17Z","timestamp":1790627957090,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>Cellular homeostais, that is normally maintained through autophagy, is disrupted in alcoholic liver disease (ALD). Because autophagy and exosome biogenesis share common elements, we hypothesized that increased exosome production in ALD may be linked to disruption of autophagic function. We found impaired autophagy both in ALD and alcoholic hepatitis (AH) mouse models and human livers with ALD as indicated by increased hepatic p62 and LC3\u2010II levels. Alcohol reduced autophagy flux <jats:italic toggle=\"yes\">in vivo<\/jats:italic> in chloroquine\u2010treated mice as well as <jats:italic toggle=\"yes\">in vitro<\/jats:italic> in hepatocytes and macrophages treated with bafilomycin A. Our results revealed that alcohol targets multiple steps in the autophagy pathway. Alcohol\u2010related decrease in mechanistic target of rapamycin (mTOR) and Ras homolog enriched in brain (Rheb), that initiate autophagy, correlated with increased Beclin1 and autophagy\u2010related protein 7 (Atg7), proteins involved in phagophore\u2010autophagosome formation, in ALD. We found that alcohol disrupted autophagy function at the lysosomal level through decreased lysosomal\u2010associated membrane protein 1 (LAMP1) and lysosomal\u2010associated membrane protein 2 (LAMP2) in livers with ALD. We identified that micro\u2010RNA 155 (miR\u2010155), that is increased by alcohol, targets mTOR, Rheb, LAMP1, and LAMP2 in the authophagy pathway. Consistent with this, miR\u2010155\u2010deficient mice were protected from alcohol\u2010induced disruption of autophagy and showed attenuated exosome production. Mechanistically, down\u2010regulation of LAMP1 or LAMP2 increased exosome release in hepatocytes and macrophages in the presence and absence of alcohol. These results suggested that the alcohol\u2010induced increase in exosome production was linked to disruption of autophagy and impaired autophagosome and lysosome function. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Alcohol affects multiple genes in the autophagy pathway and impairs autophagic flux at the lysosome level in ALD. Inhibition of LAMP1 and LAMP2 promotes exosome release in ALD. We identified miR\u2010155 as a mediator of alcohol\u2010related regulation of autophagy and exosome production in hepatocytes and macrophages.<\/jats:p>","DOI":"10.1002\/hep.30766","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T13:50:11Z","timestamp":1557928211000},"page":"2123-2141","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":190,"title":["Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro\u2010RNA 155 in Alcoholic Liver Disease"],"prefix":"10.1097","volume":"70","author":[{"given":"Mrigya","family":"Babuta","sequence":"first","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Furi","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashi","family":"Bala","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence N.","family":"Bukong","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Catalano","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Calenda","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Kodys","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyongyi","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Massachusetts Medical School,Worcester,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,6,24]]},"reference":[{"key":"hep30766-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.3748\/wjg.v16.i11.1321","article-title":"Alcoholic liver disease and the gut\u2010liver axis","volume":"16","year":"2010","journal-title":"World J Gastroenterol"},{"key":"hep30766-bib-0002-20241017","first-page":"237","article-title":"The role of innate immunity in alcoholic liver disease","volume":"37","year":"2015","journal-title":"Alcohol Res"},{"key":"hep30766-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1053\/j.gastro.2010.07.041","article-title":"Autophagy reduces acute ethanol\u2010induced hepatotoxicity and steatosis in mice","volume":"139","year":"2010","journal-title":"Gastroenterology"},{"key":"hep30766-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.jhep.2013.01.011","article-title":"Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non\u2010alcoholic fatty liver conditions in mice","volume":"58","year":"2013","journal-title":"J Hepatol"},{"key":"hep30766-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.alcohol.2014.08.006","article-title":"Impairment of autophagosome\u2010lysosome fusion contributes to chronic ethanol\u2010induced liver injury","volume":"48","year":"2014","journal-title":"Alcohol"},{"key":"hep30766-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.ajpath.2013.08.011","article-title":"Critical role of FoxO3a in alcohol\u2010induced autophagy and hepatotoxicity","volume":"183","year":"2013","journal-title":"Am J Pathol"},{"key":"hep30766-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1053\/j.gastro.2018.05.027","article-title":"Impaired TFEB\u2010mediated lysosome biogenesis and autophagy promote chronic ethanol\u2010induced liver injury and steatosis in mice","volume":"155","year":"2018","journal-title":"Gastroenterology"},{"key":"hep30766-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1258\/ebm.2011.010360","article-title":"The emerging role of autophagy in alcoholic liver disease","volume":"236","year":"2011","journal-title":"Exp Biol Med (Maywood)"},{"key":"hep30766-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1741-7007-9-39","article-title":"Following autophagy step by step","volume":"9","year":"2011","journal-title":"BMC Biol"},{"key":"hep30766-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/cdd.2008.168","article-title":"Autophagy and multivesicular bodies: two closely related partners","volume":"16","year":"2009","journal-title":"Cell Death Differ"},{"key":"hep30766-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1091\/mbc.e02-02-0114","article-title":"Role of LAMP\u20102 in lysosome biogenesis and autophagy","volume":"13","year":"2002","journal-title":"Mol Biol Cell"},{"key":"hep30766-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1002\/hep.25873","article-title":"Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug\u2010induced, and inflammatory liver diseases","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep30766-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nri855","article-title":"Exosomes: composition, biogenesis and function","volume":"2","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"hep30766-bib-0014-20241017","first-page":"403","article-title":"Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness","volume":"5","year":"2014","journal-title":"Front Immunol"},{"key":"hep30766-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nrgastro.2017.71","article-title":"Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets","volume":"14","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep30766-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"9991","DOI":"10.1038\/srep09991","article-title":"Exosomes derived from alcohol\u2010treated hepatocytes horizontally transfer liver specific miRNA\u2010122 and sensitize monocytes to LPS","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"hep30766-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.jhep.2016.01.035","article-title":"The pro\u2010inflammatory effects of miR\u2010155 promote liver fibrosis and alcohol\u2010induced steatohepatitis","volume":"64","year":"2016","journal-title":"J Hepatol"},{"key":"hep30766-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1074\/jbc.M110.145870","article-title":"Up\u2010regulation of microRNA\u2010155 in macrophages contributes to increased tumor necrosis factor alpha (TNF{alpha}) production via increased mRNA half\u2010life in alcoholic liver disease","volume":"286","year":"2011","journal-title":"J Biol Chem"},{"key":"hep30766-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"70","DOI":"10.4161\/auto.26534","article-title":"Hypoxia\u2010induced MIR155 is a potent autophagy inducer by targeting multiple players in the MTOR pathway","volume":"10","year":"2014","journal-title":"Autophagy"},{"key":"hep30766-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/hep.28680","article-title":"Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep30766-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1053\/j.gastro.2016.02.042","article-title":"Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia","volume":"150","year":"2016","journal-title":"Gastroenterology"},{"key":"hep30766-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4161\/auto.19496","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy","volume":"8","year":"2012","journal-title":"Autophagy"},{"key":"hep30766-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.febslet.2010.01.017","article-title":"mTOR regulation of autophagy","volume":"584","year":"2010","journal-title":"FEBS Lett"},{"key":"hep30766-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrm2745","article-title":"Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function","volume":"10","year":"2009","journal-title":"Nat Rev Mol Cell Biol"},{"key":"hep30766-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"10721","DOI":"10.1038\/srep10721","article-title":"Biodistribution and function of extracellular miRNA\u2010155 in mice","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"hep30766-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ejphar.2009.06.063","article-title":"Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies","volume":"625","year":"2009","journal-title":"Eur J Pharmacol"},{"key":"hep30766-bib-0027-20241017","article-title":"Monitoring and measuring autophagy","volume":"18","year":"2017","journal-title":"Int J Mol Sci"},{"key":"hep30766-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3324\/haematol.2014.113324","article-title":"Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B\u2010cell acute lymphoblastic leukemia","volume":"100","year":"2015","journal-title":"Haematologica"},{"key":"hep30766-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"E14","DOI":"10.3390\/cells6020014","article-title":"Methods for measuring autophagy in mice","volume":"6","year":"2017","journal-title":"Cells"},{"key":"hep30766-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"42712","DOI":"10.18632\/oncotarget.17448","article-title":"Characterization of mouse serum exosomal small RNA content: the origins and their roles in modulating inflammatory response","volume":"8","year":"2017","journal-title":"Oncotarget"},{"key":"hep30766-bib-0031-20241017","first-page":"E16","article-title":"mTOR pathways in cancer and autophagy","volume":"10","year":"2018","journal-title":"Cancers (Basel)"},{"key":"hep30766-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"1801313","DOI":"10.1002\/advs.201801313","article-title":"Exosome release is regulated by mTORC1","volume":"6","year":"2019","journal-title":"Adv Sci (Weinh)"},{"key":"hep30766-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2174\/1874467208666150817112654","article-title":"The activation and function of autophagy in alcoholic liver disease","volume":"10","year":"2017","journal-title":"Curr Mol Pharmacol"},{"key":"hep30766-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/nyas.13131","article-title":"Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases","volume":"1371","year":"2016","journal-title":"Ann N Y Acad Sci"},{"key":"hep30766-bib-0035-20241017","article-title":"Decreased macrophage autophagy promotes liver injury and inflammation from alcohol","year":"2019","journal-title":"Alcohol Clin Exp Res"},{"key":"hep30766-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.nbd.2011.01.029","article-title":"Lysosomal dysfunction increases exosome\u2010mediated alpha\u2010synuclein release and transmission","volume":"42","year":"2011","journal-title":"Neurobiol Dis"},{"key":"hep30766-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"13588","DOI":"10.1038\/ncomms13588","article-title":"ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins","volume":"7","year":"2016","journal-title":"Nat Commun"},{"key":"hep30766-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41467-017-02533-w","article-title":"Neuronal lysosomal dysfunction releases exosomes harboring APP C\u2010terminal fragments and unique lipid signatures","volume":"9","year":"2018","journal-title":"Nat Commun"},{"key":"hep30766-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"e0180892","DOI":"10.1371\/journal.pone.0180892","article-title":"Secretory carrier membrane protein 5 is an autophagy inhibitor that promotes the secretion of alpha\u2010synuclein via exosome","volume":"12","year":"2017","journal-title":"PLoS One"},{"key":"hep30766-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"jcs215210","DOI":"10.1242\/jcs.215210","article-title":"The interplay between exosomes and autophagy\u2014partners in crime","volume":"131","year":"2018","journal-title":"J Cell Sci"},{"key":"hep30766-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.devcel.2017.11.018","article-title":"Atg5 disassociates the V1V0\u2010ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy","volume":"43","year":"2017","journal-title":"Dev Cell"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.30766","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.30766","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.30766","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T23:52:35Z","timestamp":1729209155000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.30766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,24]]},"references-count":41,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.30766","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,24]]},"assertion":[{"value":"2018-03-30","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-07","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}