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

Tan, T.C.H., Crawford, D.H.G., Jaskowski, L.A., Subramaniam, V.N., Clouston, A.D., Crane, D.I., Bridle, K.R., Anderson, G.J., & Fletcher, L.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), pp. 1295-1312.

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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.

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29 citations in Scopus
27 citations in Web of Science®
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ID Code: 99833
Item Type: Journal Article
Refereed: No
Keywords: autophagy, endoplasmic reticulum stress, HFE, iron overload, unfolded protein response
DOI: 10.1038/labinvest.2013.121
ISSN: 1530-0307
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Facilities: Mackay Renewable Biocommodities Pilot Plant
Copyright Owner: © 2013 USCAP
Deposited On: 13 Oct 2016 04:01
Last Modified: 14 Oct 2016 05:05

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