Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Tan, Terrence C. H., Crawford, Darrell H. G., Jaskowski, Lesley A., Subramaniam,V. Nathan, Clouston, Andrew D., Crane, Denis I., Bridle, Kim R., Anderson, Gregory J. and Fletcher, Linda M. (2013) Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury. Laboratory Investigation, 93 12: 1295-1312. doi:10.1038/labinvest.2013.121


Author Tan, Terrence C. H.
Crawford, Darrell H. G.
Jaskowski, Lesley A.
Subramaniam,V. Nathan
Clouston, Andrew D.
Crane, Denis I.
Bridle, Kim R.
Anderson, Gregory J.
Fletcher, Linda M.
Title Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury
Journal name Laboratory Investigation   Check publisher's open access policy
ISSN 0023-6837
1530-0307
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/labinvest.2013.121
Open Access Status DOI
Volume 93
Issue 12
Start page 1295
End page 1312
Total pages 18
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 2734 Pathology and Forensic Medicine
1307 Cell Biology
1312 Molecular Biology
Abstract Endoplasmic reticulum (ER) stress is an important pathogenic mechanism for alcoholic (ALD) and nonalcoholic fatty liver disease (NAFLD). Iron overload is an important cofactor for liver injury in ALD and NAFLD, but its role in ER stress and associated stress signaling pathways is unclear. To investigate this, we developed a murine model of combined liver injury by co-feeding the mildly iron overloaded, the hemochromatosis gene-null (Hfe-/) mouse ad libitum with ethanol and a high-fat diet (HFD) for 8 weeks. This co-feeding led to profound steatohepatitis, significant fibrosis, and increased apoptosis in the Hfe-/-mice as compared with wild-type (WT) controls. Iron overload also led to induction of unfolded protein response (XBP1 splicing, activation of IRE-1α and PERK, as well as sequestration of GRP78) and ER stress (increased CHOP protein expression) following HFD and ethanol. This is associated with a muted autophagic response including reduced LC3-I expression and impaired conjugation to LC3-II, reduced beclin-1 protein, and failure of induction of autophagy-related proteins (Atg) 3, 5, 7, and 12. As a result of the impaired autophagy, levels of the sequestosome protein p62 were most elevated in the Hfe-/- group co-fed ethanol and HFD. Iron overload reduces the activation of adenosine monophosphate protein kinase associated with ethanol and HFD feeding. We conclude that iron toxicity may modulate hepatic stress signaling pathways by impairing adaptive cellular compensatory mechanisms in alcohol- and obesity-induced liver injury.
Keyword Autophagy
Endoplasmic reticulum stress
Iron Overload
Unfolded protein response
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 30 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 10 Dec 2013, 10:34:51 EST by System User on behalf of School of Medicine