Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets
2011; Elsevier BV; Volume: 141; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2011.09.002
ISSN1528-0012
Autores Tópico(s)Diet, Metabolism, and Disease
ResumoAlcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism–associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets. Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism–associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets. Alcohol consumption is a major risk factor for chronic disease worldwide; it accounted for 3.8% of all deaths in 2004.1Rehm J. Mathers C. Popova S. et al.Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders.Lancet. 2009; 373: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar It is also a major cause of chronic liver disease in Western countries. Alcohol-related liver deaths account for up to 48% of cirrhosis-associated deaths in the United States2Yoon Y. Yi H. Liver cirrhosis mortality in the United States, 1970–2007 surveillance report #88 NIAAA homepage 2010.http://pubs.niaaa.nih.gov/publications/surveillance88/Cirr07.htmGoogle Scholar and are also major contributors to liver disease–related mortality in other countries.1Rehm J. Mathers C. Popova S. et al.Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders.Lancet. 2009; 373: 2223-2233Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar Research on alcoholic liver disease (ALD) has been rapidly growing since the early 1960s; at that time, Lieber et al used experimental models to show that alcohol is a true hepatotoxin, which causes hepatocellular damage, and that ALD is not simply caused by malnutrition.3Lieber C.S. Jones D.P. Decarli L.M. Effects of prolonged ethanol intake: production of fatty liver despite adequate diets.J Clin Invest. 1965; 44: 1009-1021Crossref PubMed Google Scholar Early studies indicated that ethanol metabolism–associated oxidative stress, glutathione depletion, abnormal methionine metabolism, malnutrition, ethanol-mediated induction of leakage of gut endotoxins, and subsequent activation of Kupffer cells have important roles in the pathogenesis of ALD.4Lieber C.S. Susceptibility to alcohol-related liver injury.Alcohol Alcohol Suppl. 1994; 2: 315-326PubMed Google Scholar, 5Thurman R.G. Bradford B.U. Iimuro Y. et al.The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury.J Gastroenterol Hepatol. 1998; 13: S39-S50PubMed Google Scholar, 6Tsukamoto H. Lu S.C. Current concepts in the pathogenesis of alcoholic liver injury.FASEB J. 2001; 15: 1335-1349Crossref PubMed Scopus (235) Google Scholar, 7Hoek J.B. Cahill A. Pastorino J.G. Alcohol and mitochondria: a dysfunctional relationship.Gastroenterology. 2002; 122: 2049-2063Abstract Full Text Full Text PDF PubMed Google Scholar, 8Lumeng L. Crabb D.W. Alcoholic liver disease.Curr Opin Gastroenterol. 2001; 17: 211-220Crossref PubMed Scopus (17) Google Scholar, 9Arteel G. Marsano L. Mendez C. et al.Advances in alcoholic liver disease.Best Pract Res Clin Gastroenterol. 2003; 17: 625-647Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar We review advances made in the past 10 years in our understanding of the roles of lipopolysaccharide (LPS) signaling, innate immunity, and transcription factors in the pathogenesis of ALD. We also review recent studies showing that alcohol mediates changes in epigenetic features, microRNAs (miRNAs), and stem cells, which could also contribute to ALD.Despite the profound economic and health impact of ALD, little progress has been made in the management of patients with this severe clinical condition. There are no modern diagnostic tools to assess individual susceptibility to the development of ALD, and the pathogenesis of ALD in humans is incompletely understood. As a consequence, no new drugs for ALD have been successfully developed since the early 1970s, at which time the use of corticosteroids was proposed for the treatment of severe alcoholic hepatitis.10Helman R.A. Temko M.H. Nye S.W. et al.Alcoholic hepatitis Natural history and evaluation of prednisolone therapy.Ann Intern Med. 1971; 74: 311-321Crossref PubMed Google Scholar The poor therapeutic progress in the field of ALD has, in part, resulted from the lack of experimental models of advanced ALD and from difficulties in performing clinical trials in patients with an active addiction. We review several potential targets that could generate therapeutic interventions for ALD.Spectrum, Risk Factors, and ComorbiditiesALD presents as a broad spectrum of disorders, ranging from simple fatty liver to more severe forms of liver injury, including alcoholic hepatitis (AH), cirrhosis, and superimposed hepatocellular carcinoma (HCC) (Figure 1). Fatty liver, an early response to alcohol consumption, develops in most (more than 90%) heavy drinkers, with early-mild steatosis in zone 3 (perivenular) hepatocytes; it can also affect zone 2 and even zone 1 (periportal) hepatocytes when liver injury is more severe. Interestingly, only about 30% of heavy drinkers develop more severe forms of ALD, such as advanced fibrosis and cirrhosis. In patients with underlying ALD and heavy alcohol intake, episodes of superimposed AH may occur. In severe cases and in patients with liver cirrhosis, AH leads to severe complications related to liver failure and portal hypertension and has high short-term mortality.The fact that only about 35% of heavy drinkers develop advanced ALD indicates that other factors are involved. Several risk factors for ALD have been identified (Figure 1). These include sex, obesity, drinking patterns, dietary factors, non–sex-linked genetic factors, and cigarette smoking (Figure 1).11O'Shea R.S. Dasarathy S. McCullough A.J. Alcoholic liver disease.Hepatology. 2010; 51: 307-328Crossref PubMed Scopus (249) Google Scholar, 12Tsukamoto H. Machida K. Dynnyk A. et al.“Second hit” models of alcoholic liver disease.Semin Liver Dis. 2009; 29: 178-187Crossref PubMed Scopus (22) Google Scholar, 13Wilfred de Alwis N.M. Day C.P. Genetics of alcoholic liver disease and nonalcoholic fatty liver disease.Semin Liver Dis. 2007; 27: 44-54Crossref PubMed Scopus (112) Google Scholar Female sex is a well-documented risk factor for susceptibility to ALD; the increased risk among women likely results from lower levels of gastric alcohol dehydrogenase, a higher proportion of body fat, and the presence of estrogens. Obesity represents another important risk factor that accelerates fibrosis progression and the development of cirrhosis in ALD.14Raynard B. Balian A. Fallik D. et al.Risk factors of fibrosis in alcohol-induced liver disease.Hepatology. 2002; 35: 635-638Crossref PubMed Scopus (194) Google Scholar, 15Naveau S. Giraud V. Borotto E. et al.Excess weight risk factor for alcoholic liver disease.Hepatology. 1997; 25: 108-111Crossref PubMed Google Scholar Experimental studies indicate that the synergistic effects of obesity and alcohol abuse involve the endoplasmic reticulum response to cell stress, type I macrophage activation, and adiponectin resistance.16Xu J. Lai K.K. Verlinsky A. et al.Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK.J Hepatol. 2011; 55: 673-682Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Daily or near-daily heavy drinking, begun at an early age, increases the risk of the development of severe forms of ALD compared with episodic or binge drinking.17Hatton J. Burton A. Nash H. et al.Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease.Addiction. 2009; 104: 587-592Crossref PubMed Scopus (29) Google Scholar Genetic factors might also influence susceptibility to advanced ALD, but little data are available. Variations in genes that encode antioxidant enzymes, cytokines and other inflammatory mediators, and alcohol-metabolizing enzymes could have a role.13Wilfred de Alwis N.M. Day C.P. Genetics of alcoholic liver disease and nonalcoholic fatty liver disease.Semin Liver Dis. 2007; 27: 44-54Crossref PubMed Scopus (112) Google Scholar Also, recent studies indicate that variations in patatin-like phospholipase domain-containing protein 3 (PNPLA3) affect development of alcoholic cirrhosis in white alcoholic subjects.18Tian C. Stokowski R.P. Kershenobich D. et al.Variant in PNPLA3 is associated with alcoholic liver disease.Nat Genet. 2010; 42: 21-23Crossref PubMed Scopus (140) Google Scholar, 19Stickel F. Buch S. Lau K. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.Hepatology. 2011; 53: 86-95Crossref PubMed Scopus (93) Google Scholar, 20Trépo E. Gustot T. Degré D. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J Hepatol. 2011; 55: 906-912Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Despite the strong link between the PNPLA3 polymorphisms and fatty liver diseases, deletion of this gene did not affect obesity-associated fatty liver or levels of liver enzymes in mice fed a high-fat diet.21Chen W. Chang B. Li L. et al.Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease.Hepatology. 2010; 52: 1134-1142Crossref PubMed Scopus (72) Google Scholar Further studies are required to clarify the role of PNPLA3 variants in the pathogenesis of ALD.Finally, long-term alcohol drinking has synergistic effects with hepatitis virus B or C and/or human immunodeficiency virus infection, nonalcoholic fatty liver disease, and disorders such as hemochromatosis to accelerate progression of liver diseases. For example, many patients with viral hepatitis consume alcohol, which accelerates progression of liver fibrosis, cirrhosis, and HCC, likely via multiple mechanisms.22Gao B. Alcohol and hepatitis virus interactions in liver pathology Comprehensive handbook of alcohol related pathology.in: Academic Press Inc, New York2005: 819-832Google Scholar, 23Siu L. Foont J. Wands J.R. Hepatitis C virus and alcohol.Semin Liver Dis. 2009; 29: 188-199Crossref PubMed Scopus (24) Google Scholar A greater understanding of the interaction between alcohol and these comorbid factors could help us design better therapies for the treatment of chronic liver disease.PathogenesisAlcoholic Fatty Liver (Steatosis)Steatosis, the earliest response of the liver to alcohol abuse, is characterized by the accumulation of fat (mainly triglycerides, phospholipids, and cholesterol esters) in hepatocytes. Early studies indicated that alcohol consumption increases the ratio of reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide in hepatocytes, which disrupts mitochondrial β-oxidation of fatty acids and results in steatosis.24Baraona E. Lieber C.S. Effects of ethanol on lipid metabolism.J Lipid Res. 1979; 20: 289-315Abstract Full Text PDF PubMed Google Scholar Alcohol intake has also been shown to augment the supply of lipids to the liver from the small intestine, increasing mobilization of fatty acids from adipose tissue and uptake of fatty acids by the liver.24Baraona E. Lieber C.S. Effects of ethanol on lipid metabolism.J Lipid Res. 1979; 20: 289-315Abstract Full Text PDF PubMed Google Scholar However, the contribution of these mechanisms to the development of steatosis after long-term alcohol consumption is not clear and requires further investigation.Recent studies indicate that alcohol exposure, directly or indirectly, regulates lipid metabolism-associated transcription factors; this stimulates lipogenesis and inhibits fatty acid oxidation (Figure 2). Ethanol increases fatty acid synthesis in hepatocytes via up-regulation of sterol regulatory element-binding protein 1c (SREBP-1c), a transcription factor that promotes fatty acid synthesis via up-regulation of lipogenic genes. Alcohol consumption could directly increase transcription of SREBP-1c gene via its metabolite acetaldehyde25You M. Fischer M. Deeg M.A. et al.Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP).J Biol Chem. 2002; 277: 29342-29347Crossref PubMed Scopus (358) Google Scholar or indirectly up-regulate SREBP-1c expression by activating processes and factors that stimulate SREBP-1c expression, such as the endoplasmic reticulum response to cell stress,26Esfandiari F. Medici V. Wong D.H. et al.Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse.Hepatology. 2010; 51: 932-941Crossref PubMed Scopus (29) Google Scholar, 27Ji C. 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(1) Alcohol consumption can directly (via acetaldehyde) or indirectly (via regulation of multiple factors) up-regulate the expression of SREBP-1c and down-regulate the expression of PPAR-α, leading to the induction of fatty acid synthesis and inhibition of fatty liver β-oxidation, which results in the development of alcoholic fatty liver. Alcohol exposure also inhibits AMPK and subsequently increases ACC activity but decreases carnitine palmitoyltransferase 1 (CPT-1) activity, leading to an increase in fatty acid synthesis and a decrease in fatty acid β-oxidation. (2) Alcohol consumption can also modify many factors, including HIF-1, C3, C1qa, PKCε, and iNOS, that subsequently contribute to the development of fatty liver. The mechanisms underlying the effects of these factors remain unclear.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Alcohol consumption inhibits fatty acid oxidation in hepatocytes mainly via inactivation of the peroxisome proliferator-activated receptor (PPAR)-α, a nuclear hormone receptor that controls transcription of a range of genes involved in free fatty acid transport and oxidation.40Yu S. Rao S. Reddy J.K. Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis.Curr Mol Med. 2003; 3: 561-572Crossref PubMed Scopus (95) Google Scholar, 41Wagner M. Zollner G. Trauner M. Nuclear receptors in liver disease.Hepatology. 2011; 53: 1023-1034Crossref PubMed Scopus (66) Google Scholar The ethanol metabolite acetaldehyde, but not ethanol itself, directly inhibits the transcriptional activation activity and DNA-binding ability of PPAR-α in hepatocytes.42Galli A. Pinaire J. Fischer M. et al.The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism A novel mechanism for the development of ethanol-induced fatty liver.J Biol Chem. 2001; 276: 68-75Crossref PubMed Scopus (108) Google Scholar Ethanol consumption can also indirectly inhibit PPAR-α via up-regulation of cytochrome P450 2E1–derived oxidative stress43Lu Y. Zhuge J. Wang X. et al.Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice.Hepatology. 2008; 47: 1483-1494Crossref PubMed Scopus (84) Google Scholar and adenosine,28Peng Z. Borea P.A. Varani K. et al.Adenosine signaling contributes to ethanol-induced fatty liver in mice.J Clin Invest. 2009; 119: 582-594Crossref PubMed Scopus (60) Google Scholar both of which inhibit PPAR-α, or via down-regulation of adiponectin44You M. Considine R.V. Leone T.C. et al.Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice.Hepatology. 2005; 42: 568-577Crossref PubMed Scopus (136) Google Scholar and zinc,45Kang X. Zhong W. Liu J. et al.Zinc supplementation reverses alcohol-induced steatosis in mice through reactivating hepatocyte nuclear factor-4alpha and peroxisome proliferator-activated receptor-alpha.Hepatology. 2009; 50: 1241-1250Crossref PubMed Scopus (42) Google Scholar which each activate PPAR-α.In addition to regulating fat metabolism–associated transcription factors, ethanol can also affect the activities of enzymes involved in fat metabolism by inhibiting AMPK, which reduces fat metabolism and fatty liver. AMPK is a serine-threonine kinase that can phosphorylate and subsequently inactivate acetyl-CoA carboxylase (ACC), a rate-limiting enzyme for fatty acid synthesis. Inactivation of ACC also reduces levels of malonyl-CoA, a precursor in fatty acid synthesis and an inhibitor of carnitine palmitoyltransferase 1, a rate-limiting enzyme for fatty acid oxidation.46Viollet B. Guigas B. Leclerc J. et al.AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives.Acta Physiol (Oxf). 2009; 196: 81-98Crossref PubMed Scopus (141) Google Scholar In addition, AMPK directly phosphorylates and inhibits SREBP activity in hepatocytes, thereby attenuating steatosis.47Li Y. Xu S. Mihaylova M.M. et al.AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.Cell Metab. 2011; 13: 376-388Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar In this manner, AMPK inhibits fatty acid synthesis but promotes fatty acid oxidation via the inactivation of ACC enzyme activity. Alcohol consumption inhibits AMPK activity in the liver, leading to decreased phosphorylation and increased activity of ACC and decreased activity of carnitine palmitoyltransferase 1; each has an important role in the development of alcoholic fatty liver.35You M. Matsumoto M. Pacold C.M. et al.The role of AMP-activated protein kinase in the action of ethanol in the liver.Gastroenterology. 2004; 127: 1798-1808Abstract Full Text Full Text PDF PubMed Scopus (158) Google ScholarEthanol-induced steatosis is markedly reduced in many strains of mice, including HIF-1−/−,48Nath B. Levin I. Csak T. et al.Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice.Hepatology. 2011; 53: 1526-1537Crossref PubMed Scopus (39) Google Scholar C3−/−,49Pritchard M.T. McMullen M.R. Stavitsky A.B. et al.Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice.Gastroenterology. 2007; 132: 1117-1126Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar C1qa−/−,50Cohen J.I. Roychowdhury S. McMullen M.R. et al.Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.Gastroenterology. 2010; 139 (674 e1): 664-674Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar PKCε−/−,51Kaiser J.P. Beier J.I. Zhang J. et al.PKCepsilon plays a causal role in acute ethanol-induced steatosis.Arch Biochem Biophys. 2009; 482: 104-111Crossref PubMed Scopus (14) Google Scholar and iNOS,−/−52McKim S.E. Gabele E. Isayama F. et al.Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice.Gastroenterology. 2003; 125: 1834-1844Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar indicating that regulation of these genes also contributes to the pathogenesis of alcoholic fatty liver. However, the underlying mechanisms remain to be determined.Finally, autophagy has an important role in removing lipid droplets in hepatocytes.53Czaja M.J. Functions of autophagy in hepatic and pancreatic physiology and disease.Gastroenterology. 2011; 140: 1895-1908Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Long-term alcohol consumption inhibits autophagy.54Donohue Jr, T.M. Autophagy and ethanol-induced liver injury.World J Gastroenterol. 2009; 15: 1178-1185Crossref PubMed Scopus (43) Google Scholar, 55Wu D. Wang X. Zhou R. et al.CYP2E1 enhances ethanol-induced lipid accumulation but impairs autophagy in HepG2 E47 cells.Biochem Biophys Res Commun. 2010; 402: 116-122Crossref PubMed Scopus (28) Google Scholar However, a recent study showed that short-term ethanol exposure activates autophagy by generating reactive oxygen species and inhibiting the mammalian target of rapamycin, indicating that acute ethanol activation of autophagy could have a compensatory role that prevents development of steatosis during the early stages of alcoholic liver injury.56Ding W.X. Li M. Chen X. et al.Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.Gastroenterology. 2010; 139: 1740-1752Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar The inhibitory and stimulatory effects of ethanol on autophagy require further studies to clarify.AHAH is a syndrome characterized by infiltration of the liver by inflammatory cells and hepatocellular injury. AH develops in patients with steatosis and is usually associated with progressive fibrosis. The prevalence of AH has not been accurately determined; it is believed to occur in 10% to 35% of heavy drinkers. AH includes a spectrum of diseases that range from mild injury to severe, life-threatening injury.11O'Shea R.S. Dasarathy S. McCullough A.J. Alcoholic liver disease.Hepatology. 2010; 51: 307-328Crossref PubMed Scopus (249) Google Scholar, 57Lucey M.R. Mathurin P. Morgan T.R. Alcoholic hepatitis.N Engl J Med. 2009; 360: 2758-2769Crossref PubMed Scopus (210) Google Scholar The histologic characteristics of AH include centrilobular ballooning of hepatocytes, neutrophilic infiltration, Mallory–Denk hyaline inclusions, steatosis, and a “chicken wire”–like pattern of fibrosis. In many cases, there is underlying cirrhosis.11O'Shea R.S. Dasarathy S. McCullough A.J. Alcoholic liver disease.Hepatology. 2010; 51: 307-328Crossref PubMed Scopus (249) Google Scholar, 57Lucey M.R. Mathurin P. Morgan T.R. Alcoholic hepatitis.N Engl J Med. 2009; 360: 2758-2769Crossref PubMed Scopus (210) Google Scholar A large body of evidence indicates that many factors contribute to alcohol-induced inflammation (Figure 3).Figure 3Mechanisms underlying inflammation in ALD. (1) Activation of innate immunity. Parenchymal infiltration of neutrophils and macrophages is a prominent feature of ALD and is likely due to ethanol-mediated activation of innate immunity and subsequent induction of proinflammatory cytokines and chemokines. Alcohol consumption up-regulates a variety of factors that activate Kupffer cells, stellate cells, and hepatocytes, resulting in the production of cytokines and chemokines. Alcohol exposure also decreases proteasome activity and elevates IL-8 expression in hepatocytes. (2) Activation of adaptive immunity. ALD is associated with infiltration of CD4+ and CD8+ T cells in the liver. Alcohol consumption induces reactive oxygen species (ROS) and causes the formation of many protein adducts that might serve as antigens in the adaptive immune response, resulting in the accumulation of T and B cells in the liver.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Hepatotoxicity of ethanolIn hepatocytes, ethanol is primarily metabolized into acetaldehyde by alcohol dehydrogenase in the cytosol, cytochrome P450 in microsomes, and catalase in peroxisomes. Ethanol metabolism generates reactive oxygen species and causes lipid peroxidation, mitochondrial glutathione depletion, and S-adenosylmethionine depletion; all of these products subsequently prime and sensitize hepatocytes to injury. Acetaldehyde is rapidly metabolized into acetate by aldehyde dehydrogenase in mitochondria. Acetaldehyde is a reactive compound; it is highly toxic to hepatocytes because it forms a variety of protein and DNA adducts that promote glutathione depletio
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