Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis

J Toxicol Sci. 2007 Dec;32(5):453-68. doi: 10.2131/jts.32.453.


This review showed the common pathogenic mechanism in the development of non-alcoholic or alcoholic steatohepatitis. In particular, we describe the role of innate immune system and oxidative stress caused by gut-derived endotoxin. Gut-derived endotoxin plays an important role in alcoholic liver injury. It was reported that acute ethanol administration reduced activation of Kupffer cells. It is therefore possible that alcohol-induced hepatocellular damage occurs as a result of bacterial or endotoxin translocation under a reduction of the reticuloendothelial system (RES) function in alcoholic liver disease (ALD). On the other hand, recently, attention has been directed toward the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxin via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol-induced liver injury. It is generally accepted that activation of the innate immune system and increased release of proinflammatory cytokines and other mediators plays an important role in the development of ALD. It was shown that Kupffer cells activation by endotoxin via Toll-like receptor (TLR-4) is involved in alcohol-induced liver injury and that ethanol-induced oxidative stress is important in the regulation of transcription factor NF-kappaB activation and that cytokine production by Kupffer cells. TNF-alpha and free radicals are produced in early alcohol-induced liver injury. In support of this finding, the pathology caused by alcohol was blocked nearly completely in TNF-alpha receptor 1. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divides disease mechanisms into "first and second" hit. The best candidates for these second hits were considered to be oxidative stress (CYP2E1 induction) and associated lipid peroxidation and cyokines, principally, TNF-alpha. Some of the most definitive data on the importance of the innate immune system or oxidative stress in the pathogenesis of liver disease come from studies of alcoholic and non-alcoholic steatohepatitis in animals.

Publication types

  • Review

MeSH terms

  • Animals
  • Bacterial Translocation
  • Cytochrome P-450 CYP2E1 / metabolism
  • Disease Progression
  • Endotoxins / immunology
  • Endotoxins / metabolism
  • Ethanol / toxicity*
  • Fatty Liver / immunology
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Fatty Liver, Alcoholic / immunology
  • Fatty Liver, Alcoholic / metabolism*
  • Fatty Liver, Alcoholic / pathology
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / immunology
  • Gastrointestinal Tract / metabolism*
  • Gastrointestinal Tract / microbiology
  • Humans
  • Immunity, Innate / drug effects
  • Kupffer Cells / drug effects
  • Kupffer Cells / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver / immunology
  • Liver / metabolism*
  • Liver / pathology
  • Oxidative Stress / drug effects
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Endotoxins
  • Lipopolysaccharide Receptors
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Ethanol
  • Cytochrome P-450 CYP2E1