Abstract
Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH−) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH− deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH− deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH− deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.
Highlights
Chronic alcohol consumption is one of the major causes for inflammatory liver disease, initiating from fatty liver or hepatic steatosis and progressing to fibrosis, cirrhosis, and may lead to hepatocellular carcinoma and liver failure
Predominant hepatic steatosis and significant endoplasmic reticulum (ER) stress, with an increased lipid accumulation were observed only in the livers of alcohol dehydrogenase (ADH)− compared to ADH+ deer mice fed 3.5% EtOH
EtOH-fed ADH− and ADH+ deer mice groups, changes in injury marker, histology and ER stress found in the ADH− compared to ADH+ deer mice fed 3.5% EtOH could be attributed to total body burden of EtOH and/or its metabolism irrespective of hepatic cytochrome P450 2E1 (CYP2E1) expression
Summary
Chronic alcohol consumption is one of the major causes for inflammatory liver disease, initiating from fatty liver or hepatic steatosis and progressing to fibrosis, cirrhosis, and may lead to hepatocellular carcinoma and liver failure. About 30% of heavy drinkers with fatty liver may develop hepatitis, and ~4% of global mortality is related to regular heavy alcohol consumption. Alcoholic liver disease (ALD) is a serious health problem and risk factor for significant morbidity and mortality. Evidences indicate the role of endotoxins in alcoholic hepatitis and fibrosis [6,7,8]. Additional factors, such as epigenetics and the environment, influence pathogenesis of ALD [9,10,11]. The mechanism(s) and metabolic basis of ethanol (EtOH)-induced fatty liver progressing to inflammation and advanced forms of ALD, such as fibrosis and cirrhosis, are not well understood
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