{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T22:34:15Z","timestamp":1782513255127,"version":"3.54.5"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T00:00:00Z","timestamp":1630972800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>Previous work from our laboratories has identified multiple defects in endocytosis, protein trafficking, and secretion, along with altered Golgi function after alcohol administration. Manifestation of alcohol\u2010associated liver disease (ALD) is associated with an aberrant function of several hepatic proteins, including asialoglycoprotein receptor (ASGP\u2010R), their atypical distribution at the plasma membrane (PM), and secretion of their abnormally glycosylated forms into the bloodstream, but trafficking mechanism is unknown. Here we report that a small GTPase, Rab3D, known to be involved in exocytosis, secretion, and vesicle trafficking, shows ethanol (EtOH)\u2013impaired function, which plays an important role in Golgi disorganization. We used multiple approaches and cellular\/animal models of ALD, along with Rab3D knockout (KO) mice and human tissue from patients with ALD. We found that Rab3D resides primarily in <jats:italic toggle=\"yes\">trans<\/jats:italic>\u2010 and <jats:italic toggle=\"yes\">cis<\/jats:italic>\u2010faces of Golgi; however, EtOH treatment results in Rab3D redistribution from <jats:italic toggle=\"yes\">tran<\/jats:italic>s\u2010Golgi to <jats:italic toggle=\"yes\">cis\u2010medial\u2010<\/jats:italic>Golgi. Cells lacking Rab3D demonstrate enlargement of Golgi, especially its distal compartments. We identified that Rab3D is required for coat protein I (COPI) vesiculation in Golgi, and conversely, COPI is critical for intra\u2010Golgi distribution of Rab3D. Rab3D\/COPI association was altered not only in the liver of patients with ALD but also in the donors consuming alcohol without steatosis. In Rab3D KO mice, hepatocytes experience endoplasmic reticulum (ER) stress, and EtOH administration activates apoptosis. Notably, in these cells, ASGP\u2010R, despite incomplete glycosylation, can still reach cell surface through ER\u2010PM junctions. This mimics the effects seen with EtOH\u2010induced liver injury. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                           <jats:bold>\n                              :\n                           <\/jats:bold> We revealed that down\u2010regulation of Rab3D contributes significantly to EtOH\u2010induced Golgi disorganization, and abnormally glycosylated ASGP\u2010R is excreted through ER\u2010PM connections, bypassing canonical (ER\u2192Golgi\u2192PM) anterograde transportation. This suggests that ER\u2010PM sites may be a therapeutic target for ALD.<\/jats:p>","DOI":"10.1002\/hep4.1811","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T02:04:15Z","timestamp":1631066655000},"page":"374-388","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":9,"title":["Alcohol\u2010Induced Liver Injury: Down\u2010regulation and Redistribution of Rab3D Results in Atypical Protein Trafficking"],"prefix":"10.1097","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-0495","authenticated-orcid":false,"given":"Carol A.","family":"Casey","sequence":"first","affiliation":[{"name":"Department of Research Service,Omaha Western Iowa Health Care System, VA Service,Omaha,NE,USA"},{"name":"Department of Internal Medicine,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0545-1313","authenticated-orcid":false,"given":"Amanda J.","family":"Macke","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan R.","family":"Gough","sequence":"additional","affiliation":[{"name":"Department of Research Service,Omaha Western Iowa Health Care System, VA Service,Omaha,NE,USA"},{"name":"Department of Internal Medicine,University of Nebraska Medical Center,Omaha,NE,USA"},{"name":"Department of Biochemistry and Molecular Biology,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8507-0969","authenticated-orcid":false,"given":"Artem N.","family":"Pachikov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,University of Nebraska Medical Center,Omaha,NE,USA"},{"name":"The Fred and Pamela Buffett Cancer Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4148-5636","authenticated-orcid":false,"given":"Mary E.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2158-7077","authenticated-orcid":false,"given":"Paul G.","family":"Thomes","sequence":"additional","affiliation":[{"name":"Department of Research Service,Omaha Western Iowa Health Care System, VA Service,Omaha,NE,USA"},{"name":"Department of Internal Medicine,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacy L.","family":"Kubik","sequence":"additional","affiliation":[{"name":"Department of Research Service,Omaha Western Iowa Health Care System, VA Service,Omaha,NE,USA"},{"name":"Department of Internal Medicine,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa S.","family":"Holzapfel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology,University of Nebraska Medical Center,Omaha,NE,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3895-3993","authenticated-orcid":false,"given":"Armen","family":"Petrosyan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,University of Nebraska Medical Center,Omaha,NE,USA"},{"name":"The Fred and Pamela Buffett Cancer 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