Acrolein Is a Pathogenic Mediator of Alcoholic Liver Disease and the Scavenger Hydralazine Is Protective in Mice.
Cell Mol Gastroenterol Hepatol
; 2(5): 685-700, 2016 Sep.
Article
in En
| MEDLINE
| ID: mdl-28119953
ABSTRACT
BACKGROUND & AIMS:
Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality, with no Food and Drug Administration-approved therapy. Chronic alcohol consumption causes a pro-oxidant environment and increases hepatic lipid peroxidation, with acrolein being the most reactive/toxic by-product. This study investigated the pathogenic role of acrolein in hepatic endoplasmic reticulum (ER) stress, steatosis, and injury in experimental ALD, and tested acrolein elimination/scavenging (using hydralazine) as a potential therapy in ALD.METHODS:
In vitro (rat hepatoma H4IIEC cells) and in vivo (chronic+binge alcohol feeding in C57Bl/6 mice) models were used to examine alcohol-induced acrolein accumulation and consequent hepatic ER stress, apoptosis, and injury. In addition, the potential protective effects of the acrolein scavenger, hydralazine, were examined both in vitro and in vivo.RESULTS:
Alcohol consumption/metabolism resulted in hepatic accumulation of acrolein-protein adducts, by up-regulation of cytochrome P4502E1 and alcohol dehydrogenase, and down-regulation of glutathione-s-transferase-P, which metabolizes/detoxifies acrolein. Alcohol-induced acrolein adduct accumulation led to hepatic ER stress, proapoptotic signaling, steatosis, apoptosis, and liver injury; however, ER-protective/adaptive responses were not induced. Notably, direct exposure to acrolein in vitro mimicked the in vivo effects of alcohol, indicating that acrolein mediates the adverse effects of alcohol. Importantly, hydralazine, a known acrolein scavenger, protected against alcohol-induced ER stress and liver injury, both in vitro and in mice.CONCLUSIONS:
Our study shows the following (1) alcohol consumption triggers pathologic ER stress without ER adaptation/protection; (2) alcohol-induced acrolein is a potential therapeutic target and pathogenic mediator of hepatic ER stress, cell death, and injury; and (3) removal/clearance of acrolein by scavengers may have therapeutic potential in ALD.
ADH, alcohol dehydrogenase; ALD, alcoholic liver disease; ALDH, aldehyde dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATF, activating transcription factor; Apoptosis; CHOP; CHOP, CCAAT/enhancer-binding protein homologous protein; CYP2E1, cytochrome P4502E1; ER, endoplasmic reticulum; FDP-lysine, Nε-(3-formyl-3,4-dehydropiperidino)lysine; GRP, glucose regulated protein; GSTP, glutathione-s-transferase-Pi; IRE1, inositol-requiring enzyme 1; JNK, cJun N-terminal kinase; LPO, lipid peroxidation; Lipid Peroxidation; NIAAA, National Institute on Alcohol Abuse and Alcoholism; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PUFA, polyunsaturated fatty acids; TRAF, TNF receptor-associated factor; TUNEL, terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling; Therapeutic; UPR, unfolded protein response; XBP1, X-box binding protein-1; mRNA, messenger RNA; siRNA, small interfering RNA
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Cell Mol Gastroenterol Hepatol
Year:
2016
Document type:
Article