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Binge alcohol promotes acute liver injury through a CYP2E1‐HIF‐1α‐dependent apoptosis pathway in mice and humans (1010.1)
Author(s) -
Yun JunWon,
Son MinJeong,
Abdelmegeed Mohamed,
Banerjee Atrayee,
Morgan Timothy,
Yoo SeongHo,
Song ByoungJoon
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1010.1
Subject(s) - cyp2e1 , apoptosis , binge drinking , alcohol , alcoholic liver disease , medicine , endocrinology , liver injury , chemistry , biology , cancer research , biochemistry , cytochrome p450 , cirrhosis , alcohol consumption , metabolism
Binge drinking, a common pattern of alcohol intake, has been known to amplify liver injury caused by chronic alcohol abuse. This study was aimed to investigate if and how binge alcohol activates hepatic hypoxia‐inducible factor 1α (HIF‐1α) and its downstream target associated with apoptosis and protein nitration. We analyzed mice treated with three ethanol doses and autopsied human specimens selected as binge or non‐binge group. We observed positive correlations among blood alcohol concentration (BAC), cytochrome P450 2E1 (CYP2E1) and HIF‐1α in mice and humans exposed to binge alcohol. The expressed levels and activities of CYP2E1 showed significantly higher correlation with BACs in humans. HIF‐1α levels were also positively correlated with BACs or CYP2E1 activities in humans. Consistently with HIF‐1α activation, binge alcohol also promoted hepatocyte apoptosis and hepatic protein nitration. Particularly, significant correlations of hepatic iNOS and 3‐nitrotyrosine formation were found with BACs, CYP2E1 and HIF‐1α in humans. The HIF‐1α activation and its apoptosis‐ or protein nitration‐related downstream targets were significantly alleviated in binge alcohol‐exposed Cyp2e1‐null mice, suggesting the role of CYP2E1 in HIF‐1α‐associated apoptosis and protein nitration. Binge alcohol promotes acute liver injury in mice and humans through a CYP2E1‐HIF‐1α‐dependent apoptosis pathway.