In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 11 ( 2022-11-15), p. e0276879-
Abstract:
Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2 KO ) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12 , Lamp1 , Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His 123 , Cys 128 , His 174 , His 181 , Lys 238 , Cys 290 , His 340 , Lys 341 and His 385 . These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0276879
DOI:
10.1371/journal.pone.0276879.g001
DOI:
10.1371/journal.pone.0276879.g002
DOI:
10.1371/journal.pone.0276879.g003
DOI:
10.1371/journal.pone.0276879.g004
DOI:
10.1371/journal.pone.0276879.g005
DOI:
10.1371/journal.pone.0276879.g006
DOI:
10.1371/journal.pone.0276879.g007
DOI:
10.1371/journal.pone.0276879.g008
DOI:
10.1371/journal.pone.0276879.g009
DOI:
10.1371/journal.pone.0276879.t001
DOI:
10.1371/journal.pone.0276879.t002
DOI:
10.1371/journal.pone.0276879.s001
DOI:
10.1371/journal.pone.0276879.s002
DOI:
10.1371/journal.pone.0276879.s003
DOI:
10.1371/journal.pone.0276879.s004
DOI:
10.1371/journal.pone.0276879.s005
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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