{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T11:40:12Z","timestamp":1780054812752,"version":"3.54.0"},"reference-count":32,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2017,2,8]],"date-time":"2017-02-08T00:00:00Z","timestamp":1486512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NIAAA","award":["U021898"],"award-info":[{"award-number":["U021898"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory\u2013Denk body (MDB) formation develops in the hepatocytes in alcoholic hepatitis as a consequence of the failure of these protein quality control mechanisms to remove misfolded and damaged proteins and to prevent MDB aggresome formation within the cytoplasm of hepatocytes. The proteins involved in the quality control pathways are identified, quantitated, and visualized by immunofluorescent antibody staining of liver biopsies from patients with AH. Quantification of the proteins are achieved by measuring the fluorescent intensity using a morphometric system. Ufmylation and FAT10ylation pathways were downregulated, Mca1 pathways were upregulated, autophagocytosis was upregulated, and ER stress PERK (protein kinase RNA-like endoplasmic reticulum kinase) and CHOP (CCAAT\/enhancer-binding protein homologous protein) mechanisms were upregulated. In conclusion: Despite the upregulation of several pathways of protein quality control, aggresomes (MDBs) still formed in the hepatocytes in AH. The pathogenesis of AH is due to the failure of protein quality control, which causes balloon-cell change with MDB formation and ER stress.<\/jats:p>","DOI":"10.3390\/biom7010011","type":"journal-article","created":{"date-parts":[[2017,2,10]],"date-time":"2017-02-10T05:27:09Z","timestamp":1486704429000},"page":"11","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis"],"prefix":"10.3390","volume":"7","author":[{"given":"Samuel","family":"French","sequence":"first","affiliation":[{"name":"Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA"},{"name":"LA BioMed Research Institute, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Masouminia","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Samadzadeh","sequence":"additional","affiliation":[{"name":"LA BioMed Research Institute, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Tillman","sequence":"additional","affiliation":[{"name":"LA BioMed Research Institute, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Mendoza","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"French","sequence":"additional","affiliation":[{"name":"LA BioMed Research Institute, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.yexmp.2014.05.010","article-title":"UFmylation and FATylation pathways are downregulated in human alcoholic and steatohepatitis and mice fed DDC, where Mallory-Denk bodies (MDBs) form","volume":"97","author":"Liu","year":"2014","journal-title":"Exp. Mol. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yexmp.2010.04.001","article-title":"The role of cytokines in UBD promoter regulation and Mallory-Denk body-like aggresomes","volume":"89","author":"Oliva","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.yexmp.2010.03.001","article-title":"SAMe prevents the induction of the immunoproteasome and preserves the 26S proteasome in the DDC induced MDB mouse model","volume":"88","author":"Oliva","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.yexmp.2012.09.002","article-title":"FAT10 Knockout Mice Livers Fail to develop Mallory-Denk Bodies in the DDC Mouse Model","volume":"93","author":"French","year":"2012","journal-title":"Exp. Mol. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.yexmp.2014.10.001","article-title":"Mallory-Denk Body (MDB) formation modulation Ufmylation expression epigenetically in alcoholic hepatitis (AH) and non-alcoholic hepatitis (NASH)","volume":"97","author":"Liu","year":"2014","journal-title":"Exp. Mol. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.yexmp.2008.11.002","article-title":"Betaine prevents Mallory-Denk body formation in drug-primed mice by epigenetic mechanisms","volume":"86","author":"Oliva","year":"2009","journal-title":"Exp. Mol. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.yexmp.2007.12.004","article-title":"Epigenetic mechanisms regulate Mallory-Denk body formation in the livers of drug-primed mice","volume":"84","author":"Oliva","year":"2008","journal-title":"Exp. Mol. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.yexmp.2014.12.003","article-title":"Levels of metacaspase 1 and chaperones related to protein quality control in alcoholic and nonalcoholic steatohepatitis","volume":"98","author":"Mendoza","year":"2015","journal-title":"Exp. Mol. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1126\/science.1252634","article-title":"Life-span extension by a metacaspase in the yeast Saccharomyces cerevisiae","volume":"344","author":"Hill","year":"2014","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1083\/jcb.200507002","article-title":"p62\/SQSTM1 forms protein aggregates degraded by autophages and has a protective effect on huntingtin-induced cell death","volume":"171","author":"Bjerkey","year":"2005","journal-title":"J. Cell. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1128\/MCB.16.9.4773","article-title":"Involvement of the molecular chaperone Ydj1 in the ubiquitin-dependent degradation of short-lived and abnormal proteins in Saccharomyces cerevisiae","volume":"16","author":"Lee","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jsb.2012.03.003","article-title":"Expanding into new markets-VCP\/p97 in endocytosis and autophagy","volume":"179","author":"Bug","year":"2012","journal-title":"J. Struct. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/nature07195","article-title":"Misfolded protein partition between two distinct quality control compartments","volume":"454","author":"Kaganovich","year":"2008","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1534-5807(03)00296-X","article-title":"A unified nomenclature for yeast autophagy-related genes","volume":"5","author":"Klonsky","year":"2003","journal-title":"Dev. Cell."},{"key":"ref_15","first-page":"1016","article-title":"Dynamics and diversity in autophagy mechanisms: Lesions from yeast","volume":"9","author":"Nakatogawa","year":"2011","journal-title":"Rev. Molec. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/ncb2329","article-title":"The AMPK signaling pathway coordinates cell growth, autophagy and metabolism","volume":"13","author":"Miyaylova","year":"2011","journal-title":"Natl. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1083\/jcb.200712064","article-title":"FIP200, a ULK-interacting protein, is required for autophagasome formation in mammalian cells","volume":"181","author":"Hara","year":"2008","journal-title":"J. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.canlet.2016.01.022","article-title":"Unveiling the roles of ATG4 proteases from autophagy modulation in targeted cancer therapy","volume":"373","author":"Zhang","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.jhep.2010.07.006","article-title":"Autophagy in liver diseases","volume":"53","author":"Routou","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.yexmp.2016.07.002","article-title":"Up reduction of autophagia components in alcoholic hepatitis and non-alcoholic hepatitis","volume":"101","author":"Masouminia","year":"2016","journal-title":"Exp. Mol. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1002\/hep.24279","article-title":"The contribution of endoplasmic reticulum stress to liver diseases","volume":"53","author":"Kaplowitz","year":"2011","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.yexmp.2016.08.002","article-title":"Alcoholic steatohepatitis (ASH) causes more UPR-ER stress than non-alcoholic steatohepatitis","volume":"101","author":"Masouminia","year":"2016","journal-title":"Exp. Mol. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1006\/scdb.1999.0315","article-title":"Protein folding in the ER","volume":"10","author":"Stevens","year":"1999","journal-title":"Semin. Cell. Dev."},{"key":"ref_25","unstructured":"Mullins, C. (2005). The Biogenesis of Cellular Organelles, Springer. [1st ed.]."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/16729","article-title":"Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase","volume":"197","author":"Hardinig","year":"1999","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","article-title":"Regulated translated initiation controls stress-induced gene expression in mammalian cells","volume":"6","author":"Harding","year":"2000","journal-title":"Mol. Cell."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.cell.2007.04.027","article-title":"ER stress triggers apoptosis by activating BH3-only protein Bim","volume":"129","author":"Puthalakath","year":"2008","journal-title":"Cell"},{"key":"ref_29","first-page":"20108","article-title":"Perk-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress","volume":"279","author":"Cullman","year":"2007","journal-title":"J. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/jb\/mvr143","article-title":"Chop is a multifunctional transcription factor in the ER stress response","volume":"151","author":"Nishitoh","year":"2012","journal-title":"J. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.yexmp.2014.08.006","article-title":"The inflammasome in alcoholic hepatitis: Its relationship with Mallory-Denk body formation","volume":"97","author":"Peng","year":"2014","journal-title":"Exp. Mol. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42491","DOI":"10.18632\/oncotarget.6382","article-title":"Aberrant modulation of the BRCA1 and G1\/S cell cycle pathways in alcoholic hepatitis patients with Mallory Denk Bodies revealed by RNA sequencing","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/7\/1\/11\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:40Z","timestamp":1760207260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/7\/1\/11"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,8]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,3]]}},"alternative-id":["biom7010011"],"URL":"https:\/\/doi.org\/10.3390\/biom7010011","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,8]]}}}