Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis

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.

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…42,43). Our combined analysis, as well as a more limited study (68), demonstrated DPT upregulation in the liver of NASH patients. This finding was not confirmed in a recent cross-species transcriptomic study, which relied on a cohort stratification based on the composite NAS score; this score does not isolate the fibrosis component of the disease (69) and therefore precludes the detection of altered Dpt expression (Supplemental Figure 9).…”

Gut microbiome and nonalcoholic fatty liver diseases

“…In 2009, our group completed the first global gene expression analysis of NASH livers and normal controls (http://www.ncbi.nlm. nih.gov/geo/query/acc.cgi?acc=GSE17470), and found that many of the alcohol and aldehyde dehydrogenases are among the most up-regulated genes in NASH livers (41). Additionally, other alcohol metabolizing mechanisms including CYP2E1 and catalase are also highly elevated in NASH livers.…”

“…Overall, these studies suggest that, endotoxemia is not required in the pathogenesis of NASH. Endotoxemia may contribute to disease progression in some NASH cases, but other challenges such as gut derived alcohol (39,41), endoplasmic reticulum stress, and adipose tissue derived threats may cause NASH independently from endotoxemia. Our observations highlight the current "multi-hit" hypothesis for the pathogenesis of NASH (69).…”

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

“…The increased expression of CYP2E1 results in oxidative stress and production of ROS. The toxic metabolites of ethanol along with ROS may contribute to the development of steatohepatitis (17)(18)(19). In both human and rat liver, CYP2E1 is expressed predominantly in acinar zone 3 (18).…”