Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet.
OBJECTIVE
Alcoholic liver disease is associated with nutritional deficiency and it may aggravate within the context of fatty liver. We investigated the relationship between alcohol intake (whiskey binge drinking) and a choline-deficient diet (CD) and assessed whether stellate cells could contribute to liver injury in this model.


RESULTS
Rats fed the CD diet plus whiskey showed increased liver damage compared to rats fed the CD diet, as demonstrated by H&E staining, elevated transaminases, steatosis, TNF-alpha levels, enhanced CYP2E1 activity, impaired antioxidant defense, elevated lipid peroxidation, and protein carbonyls. The combined treatment triggered an apoptotic response as determined by elevated Bax, caspase-3 activity, cytochrome-c release, and decreased Bcl-2 and Bcl-XL. Stellate cells were activated as increased expression of alpha-Sma was observed over that by the CD diet alone. The combined treatment shifted extracellular matrix remodeling towards a pro-fibrogenic response due to up-regulation of collagen I, TIMP1, and Hsp47 proteins, along with down-regulation of MMP13, MMP2, and MMP9 expression, proteases which degrade collagen I. These events were accompanied by increased phosphorylation of p38, a kinase that elevates collagen I.


CONCLUSIONS
Repeated alcohol binges in the context of mild steatosis may promote activation of stellate cells and contribute to liver injury.
Nieto
Natalia
N
Mount Sinai School of Medicine, Department of Medicine, Division of Liver Diseases, New York, NY, USA. natalia.nieto@mssm.edu
Rojkind
Marcos
M
D000434:Alcoholic Beverages / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000032:analysis / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism; D002794:Choline / Q000008:administration & dosage / Q000378:metabolism*; D002796:Choline Deficiency / Q000150:complications*; D017364:Collagenases / Q000032:analysis / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000378:metabolism; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D004032:Diet; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D019392:Cytochrome P-450 CYP2E1; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; D002794:Choline