Elsevier

Alcohol

Volume 34, Issue 1, August 2004, Pages 81-87
Alcohol

Article
Obesity and alcoholic liver disease

https://doi.org/10.1016/j.alcohol.2004.07.010Get rights and content

Abstract

Obesity potentiates the severity of alcohol-induced liver damage. Ethanol influences adipose tissue production of hormones and cytokines. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis are beginning to be studied. Exacerbation of the proinflammatory state that induces tumor necrosis factor activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. Both hepatocyte apoptosis and necrosis are likely, but further study is needed to develop optimal hepatoprotective strategies. It is currently unclear whether the hepatotoxic consequences of obesity and ethanol ingestion are additive or synergistic. This information has important prognostic implications and might be useful to formulate body mass index–based guidelines for “safe” alcohol consumption. Findings of studies in experimental animals also raise questions about the relation between steatohepatitis and cirrhosis. Despite overwhelming evidence that obesity promotes alcohol-induced steatosis and steatohepatitis, most obese human beings (and mice) who drink alcohol do not become cirrhotic. Moreover, at least in mice, even severe steatohepatitis leads to cirrhosis relatively infrequently. Thus, it is conceivable that, although steatohepatitis is a permissive factor for cirrhosis, it is neither necessary nor sufficient for cirrhosis to occur. The quest to identify the proximal mediators of hepatic fibrosis should probably include an investigation of how various adipokines, neurotransmitters, and cytokines interact to regulate hepatic stellate cells. Armed with such knowledge, further modifying actions of ethanol on these mechanisms can be explored by investigators.

Introduction

Alcohol-induced liver disease remains one of the most common and deadly causes of chronic liver disease (Sussman et al., 2002). Given that alcohol is the most commonly abused substance in the United States (Szabo, 2003), it is fortunate that serious liver disease does not develop in most individuals who consume alcohol habitually (Lelbach, 1976, Morgan, 1994, Pequignot et al., 1978). However, results of several population-based studies raise concern that both the prevalence and the severity of alcohol-induced liver disease may be rising in conjunction with the obesity epidemic. Multivariate regression analysis consistently identifies obesity as an independent risk factor for alcohol-induced liver damage. Indeed, obesity seems to increase all stages of alcoholinduced liver disease, including alcoholic fatty liver, alcoholic steatohepatitis, and alcoholic cirrhosis (Bellentani et al., 2000, Naveau et al., 1997, Raynard et al., 2002).

Section snippets

Fat physiology

The liver and adipose tissue interact to regulate fat homeostasis. Adipose tissue is both a source of fatty acids that are delivered to the liver and a storage depot for triglycerides that are produced by liver and released into the bloodstream. During the past several years, it has become apparent that fat also plays a very active role in regulating both intermediary metabolism and immunity by producing a variety of pluripotent soluble factors, including adipokines (e.g., leptin, resistin, and

Fat factors modulate wound healing

Although the absence of leptin is one of the situations that promotes visceral adiposity and adipokine–cytokine abnormalities that cause hepatic injury and inflammation (i.e., steatohepatitis), a normal fibrogenic response to liver injury does not occur when leptin is absent. Thus, hepatotoxin-treated or Schistosoma-treated ob/ob mice exhibit significantly less liver fibrosis than do similarly treated, leptin-sufficient litter mate controls (Ikejima et al., 2001, Ikejima et al., 2002, Leclercq

Summary and unanswered questions

Obesity potentiates the severity of alcohol-induced liver damage. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis have been studied most extensively. Exacerbation of the proinflammatory state that induces TNF-α activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. There are proponents for increased hepatocyte apoptosis, as

Acknowledgments

This work was supported by the following NIH grants: AA010154-08S1, AA012059-04, and DK53792-04A2.

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