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Biomolecules 2017, 7(1), 11;

Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis

Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA
LA BioMed Research Institute, Torrance, CA 90502, USA
Author to whom correspondence should be addressed.
Academic Editor: Jürg Bähler
Received: 7 November 2016 / Revised: 26 January 2017 / Accepted: 30 January 2017 / Published: 8 February 2017
(This article belongs to the Collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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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–Denk 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. View Full-Text
Keywords: protein quality control; FATylation; ufmylation; Mallory–Denk bodies; metacaspase 1; autophagocytosis; ER stress; PERK; CHOP protein quality control; FATylation; ufmylation; Mallory–Denk bodies; metacaspase 1; autophagocytosis; ER stress; PERK; CHOP

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French, S.W.; Masouminia, M.; Samadzadeh, S.; Tillman, B.C.; Mendoza, A.; French, B.A. Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis. Biomolecules 2017, 7, 11.

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