Pathways of liver injury in alcoholic liver disease
Authors: Herbert Tilg, Alexander R. Moschen, Nicole C. Kaneider
Journal: Journal of Hepatology (2011)

The development of ethanol-induced liver injury including liver cirrhosis and severe alcoholic steatohepatitis (ASH) is a complex process involving various liver cell types and mainly factors released under the control of the innate immune system. Chronic ethanol consumption induces oxidative stress and production of reactive oxygen species (ROS), cytokine release, mitochondrial dysfunction, endoplasmic reticulum stress, and others. ROS initiate lipid peroxidation that directly damages plasma and intracellular membranes and leads to the production of reactive aldehydes with potent pro-inflammatory and pro-fibrotic properties. Oxidative stress and ROS are predominantly generated through the induction of cytochrome P450-2E1 (CYP2E1). A key role for this enzyme in ethanol-induced liver injury has been demonstrated by its inhibition through chlormethiazole and by the finding that CYP2E1 knock-out (KO) mice do not show evidence of ethanol-induced liver disease [[1]Lu Y. Zhuge J. Wang X. Bai J. Cederbaum A.I. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice.Hepatology. 2008; 47: 1483-1494Crossref PubMed Scopus (247) Google Scholar]. Furthermore, transgenic overexpression of human CYP2E1 in a mouse model results in more severe liver disease. Both the hydroxyethyl radical and acetaldehyde, the first products of ethanol metabolism, can bind glutathione (GSH), a tripeptide that acts as a direct free radical scavenger. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protects cells against xenobiotic and oxidative stress. Nrf2 KO mice exhibit a dramatically increased mortality after ethanol feeding, highlighting the important role of oxidative stress in ethanol-induced injury [[1]Lu Y. Zhuge J. Wang X. Bai J. Cederbaum A.I. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice.Hepatology. 2008; 47: 1483-1494Crossref PubMed Scopus (247) Google Scholar] (Fig. 1). Kupffer cells are of particular importance in ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to the activation by lipopolysaccharides (LPS) via toll-like receptor 4 (TLR4) [[2]Hritz I. Mandrekar P. Velayudham A. Catalano D. Dolganiuc A. Kodys K. et al.The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.Hepatology. 2008; 48: 1224-1231Crossref PubMed Scopus (341) Google Scholar]. This sensitization enhances the production of various pro-inflammatory mediators, such as tumor necrosis factor-α (TNFα) and ROS that contribute to hepatocyte dysfunction, necrosis and apoptosis of hepatocytes, and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis [[3]Tilg H. Diehl A.M. Cytokines in alcoholic and nonalcoholic steatohepatitis.N Engl J Med. 2000; 343: 1467-1476Crossref PubMed Scopus (853) Google Scholar]. Apoptosis, a major form of cell death, has been observed in a diverse spectrum of liver diseases. In experimental models and isolated hepatocytes, alcohol has been shown to induce liver cell apoptosis. Interestingly, the extent of apoptosis is correlated with clinical disease activity. TNFα has emerged as a key factor in various aspects of liver diseases being able to mediate many clinical aspects of severe ASH such as anorexia, fever, wasting, hypoalbuminemia, and neutrophilia. Some of the most definitive data about the importance of TNFα in the pathogenesis of liver disease have come from studies of alcoholic liver injury in animals whereas clinical studies blocking this cytokine in human studies of severe ASH have so far not proven successful. Plasma levels of both TNF and soluble TNF receptors are correlated with endotoxemia, impaired intestinal permeability, stage of liver disease, and mortality. Alcohol-associated liver injury is inhibited when the animals are treated with poorly absorbed oral antibiotics or lactobacillus to decrease endotoxemia, supporting the hypothesis that gut-derived bacterial products such as endotoxin might be important in activation of Kupffer cells and/or other cell types in the liver. This is in accordance with the recent observation that chronic ethanol feeding causes more severe liver injury in wild-type mice than in CD14 knock-outs [[4]Yin M. Bradford B.U. Wheeler M.D. Uesugi T. Froh M. Goyert S.M. et al.Reduced early alcohol-induced liver injury in CD14-deficient mice.J Immunol. 2001; 166: 4737-4742Crossref PubMed Scopus (215) Google Scholar]. These results further support the notion that gut-derived endotoxin acting via its cellular receptor CD14 plays a major role in the development of early alcohol-induced liver injury. Other pro-inflammatory cytokines, however, might be of equal importance. Serum/plasma concentrations of IL-1, IL-6, and IL-8 have been shown to be increased initially in hospitalized patients with alcoholic steatohepatitis and to decline during recovery. Enhanced serum IL-1 activity has been demonstrated in patients with severe ASH more than 20 years ago. Hepatic expression of IL-8, the critical chemokine being responsible for neutrophil recruitment into the liver, correlates with progression of patients with alcoholic hepatitis further supporting the importance of cytokine circuits in those diseases [[5]Dominguez M. Miquel R. Colmenero J. Moreno M. Garcia-Pagan J.C. Bosch J. et al.Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis.Gastroenterology. 2009; 136: 1639-1650Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. IL-17, another pro-inflammatory cytokine affecting neutrophil recruitment, is also highly activated in human alcoholic liver disease and correlates with amount of liver inflammation [[6]Lemmers A. Moreno C. Gustot T. Marechal R. Degre D. Demetter P. et al.The interleukin-17 pathway is involved in human alcoholic liver disease.Hepatology. 2009; 49: 646-657Crossref PubMed Scopus (312) Google Scholar] (Fig. 1). Anti-inflammatory protective strategies may be of critical importance to protect the liver against ethanol toxicity. Adiponectin, one of the most relevant anti-inflammatory adipocytokines in humans, circulates at high concentrations in healthy humans and chronic ethanol feeding decreases adiponectin secretion by subcutaneous adipocytes. Adiponectin improves both alcoholic and nonalcoholic fatty liver diseases in mice [[7]Xu A. Wang Y. Keshaw H. Xu L.Y. Lam K.S. Cooper G.J. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.J Clin Invest. 2003; 112: 91-100Crossref PubMed Scopus (1161) Google Scholar]. Alcoholic fatty liver is associated with decreased adiponectin levels, decreased expression of hepatic adiponectin receptors, and impaired adiponectin liver signaling in animals. Decreased adiponectin availability may contribute not only to hepatic steatosis but also to development of liver inflammation. Kupffer cells from ethanol-fed rats are highly sensitive to inhibition by adiponectin and this effect involves an IL-10/Stat3/heme oxygenase-1 pathway. Importantly, via such a mechanism, TLR4-dependent cytokine expression in rat Kupffer cells and in mouse livers after chronic ethanol exposure is suppressed. However, besides these pathways, others may be of relevance such as adenosine. Blockade of adenosine receptors type 2B decreases TNFα and IL-6 release in sepsis models. Indeed, adenosine signaling via this receptor contributes to ethanol-induced fatty liver in animals and targeting this receptor may be effective in treatment of ethanol-associated liver inflammation [[8]Peng Z. Borea P.A. Varani K. Wilder T. Yee H. Chiriboga L. et al.Adenosine signaling contributes to ethanol-induced fatty liver in mice.J Clin Invest. 2009; 119: 582-594Crossref PubMed Scopus (143) Google Scholar]. Evidence from rat studies indicates that ethanol-induced gut leakiness/hyperpermeability and endotoxemia precede liver inflammation suggesting that, indeed, ethanol-induced gut damage comes first [[9]Keshavarzian A. Farhadi A. Forsyth C.B. Rangan J. Jakate S. Shaikh M. et al.Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats.J Hepatol. 2009; 50: 538-547Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar] (Fig. 1). Even though the described cytokine dysregulations in fatty liver diseases may reflect a secondary phenomena, blockade of these highly pro-inflammatory molecules remains an attractive treatment concept. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Supported by a grant from the Austrian Science Foundation (P21530) and the Christian-Doppler Research Society.