Impact of chronic ethanol on the hormonal activity of adipose tissue

Abstract

Background and Objectives: Consumption of alcohol has been in existence in the world for many centuries. Every year the use of alcohol kills 2.5 million people accounting for almost 4% of the deaths in the world. Progression of alcoholic liver disease is a multifactorial process involving a number of genetic, nutritional and environmental factors. Alcohol is metabolized via alcohol dehydrogenase pathway, the microsomal ethanol-oxidizing system involving the Cytochrome P450 2E1 (CYP2E1) enzyme, and catalase pathway. Chronic ethanol consumption activates CYP2E1 enzyme resulting in reactive oxygen species formation leading to oxidative stress and endoplasmic reticulum stress. Excessive oxidative stress results in membrane lipid peroxidation and formation of toxic aldehydes. We hypothesize that ethanol induced oxidative and endoplasmic reticulum stress disrupt the secretion of adipokines from adipose tissue and adipokines are known to play a major role in the progression of alcoholic liver disease. Objectives: 1. Studying the over expression and inhibition of CYP2E1 on ethanol induced oxidative stress and on adipokine levels. 2. Investigating the effects of ethanol on the endoplasmic reticulum (ER) function and the influence of ER stress on the posttranslational modifications of adipokines. 3. Identification of protein adducts formed by lipid peroxidation products and investigating the resistance to the metabolic actions of adipokines by hepatic nonparenchymal cells. Results: Several passages of 3T3L1 cell line and RAW 264.7 cell line were established. The cell lines were exposed to different concentrations of ethanol. Preliminary data pertaining to the oxidative stress markers was obtained. Quantitative real time PCR studies of CYP2E1, IL-6, leptin, resistin genes are being carried out. Conclusion: Understanding the molecular mechanisms of ethanol mediated liver injury will aid in identification of new integrative approaches as it relates to alcoholic liver injury and provide potential new directions to develop therapeutic target intervention.