title: Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury.
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.
authors.affiliation: 1] School of Medicine, University of Queensland, Brisbane, QLD, Australia [2] Gallipoli Medical Research Centre, Greenslopes Hospital, Brisbane, QLD, Australia [3] Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia.
authors.forename: Terrence C H
authors.initials: TC
authors.lastname: Tan
authors.forename: Darrell H G
authors.initials: DH
authors.lastname: Crawford
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Jaskowski
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Denis I
authors.initials: DI
authors.lastname: Crane
authors.forename: Kim R
authors.initials: KR
authors.lastname: Bridle
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: Linda M
authors.initials: LM
authors.lastname: Fletcher
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005235:Fatty Liver, Alcoholic / Q000097:blood / Q000209:etiology* / Q000473:pathology; D007501:Iron / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000150:complications*; D011897:Random Allocation; D051193:Toll-Like Receptors / Q000378:metabolism; D014131:Trace Elements / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D051193:Toll-Like Receptors; D014131:Trace Elements; D007501:Iron