PMID- 24126888
OWN - NLM
STAT- MEDLINE
DCOM- 20140128
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Linking)
VI  - 93
IP  - 12
DP  - 2013 Dec
TI  - Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse 
      model of alcohol and high-fat diet-induced liver injury.
PG  - 1295-312
LID - 10.1038/labinvest.2013.121 [doi]
AB  - 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-1alpha 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.
FAU - Tan, Terrence C H
AU  - Tan TC
AD  - 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.
FAU - Crawford, Darrell H G
AU  - Crawford DH
FAU - Jaskowski, Lesley A
AU  - Jaskowski LA
FAU - Subramaniam, V Nathan
AU  - Subramaniam VN
FAU - Clouston, Andrew D
AU  - Clouston AD
FAU - Crane, Denis I
AU  - Crane DI
FAU - Bridle, Kim R
AU  - Bridle KR
FAU - Anderson, Gregory J
AU  - Anderson GJ
FAU - Fletcher, Linda M
AU  - Fletcher LM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131014
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (Hspa5 protein, mouse)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (Trace Elements)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Alcohol Drinking/adverse effects/blood
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Diet, High-Fat/adverse effects
MH  - *Disease Models, Animal
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Fatty Liver, Alcoholic/blood/*etiology/pathology
MH  - Iron/administration & dosage/*adverse effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Obesity/blood/*complications
MH  - Random Allocation
MH  - Toll-Like Receptors/metabolism
MH  - Trace Elements/administration & dosage/*adverse effects/metabolism
EDAT- 2013/10/16 06:00
MHDA- 2014/01/29 06:00
CRDT- 2013/10/16 06:00
PHST- 2013/06/26 00:00 [received]
PHST- 2013/09/16 00:00 [revised]
PHST- 2013/09/18 00:00 [accepted]
PHST- 2013/10/16 06:00 [entrez]
PHST- 2013/10/16 06:00 [pubmed]
PHST- 2014/01/29 06:00 [medline]
AID - S0023-6837(22)00872-8 [pii]
AID - 10.1038/labinvest.2013.121 [doi]
PST - ppublish
SO  - Lab Invest. 2013 Dec;93(12):1295-312. doi: 10.1038/labinvest.2013.121. Epub 2013 
      Oct 14.