Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis

Susan S Baker,Robert D Baker,Lixin Zhu,Norma J Nowak,Wensheng Liu,Christian Gluud

doi:10.1371/journal.pone.0009570

Abstract

BackgroundNon-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals.Methodology/Principal FindingsTo investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4).Conclusions/SignificanceThe augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD.

Highlights

Non-alcoholic steatohepatitis (NASH) is a serious form of nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis associated with evidence of inflammation and variable degrees of fibrosis [1]
Conclusions/Significance: The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation
Gene transcription of NASH livers was examined by a whole genome DNA microarray and quantitative real-time PCR (qRT-PCR) techniques

Summary

Introduction

Non-alcoholic steatohepatitis (NASH) is a serious form of nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis associated with evidence of inflammation and variable degrees of fibrosis [1]. Studies with NASH patients and various animal models in the last decade have revealed insights into liver fat infiltration, damage, inflammation and fibrosis. Insulin resistance (IR) seems to be a major reason for fat deposition in liver by way of uncontrolled lipolysis in adipose tissue leading to increased levels of circulating free fatty acids [4]. Measurement with stable isotopes in NAFLD patients indicated that free fatty acids are the major source for fat accumulation in liver. Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals

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Conclusion