Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the most frequent chronic liver disorders, and their advanced forms - alcoholic steatohepatitis and nonalcoholic steatohepatitis - are the most frequent conditions leading to liver cirrhosis and hepatocellular carcinoma worldwide. NAFLD is considered as the hepatic manifestation of the metabolic syndrome. With the pandemic rise of obesity, the incidence of NAFLD is also further increasing, and considering the life style in modern societies, there is a significant overlap of (risk factors causing) NAFLD and (alcohol consumption predisposing for) ALD at least in Western countries. Epidemiological studies propose a causative link between chronic alcohol consumption and progressive liver disease in obese individuals. Furthermore, experimental studies indicate combined pathological effects of alcohol and obesity or fatty acid levels, respectively, on hepatocellular lipid accumulation and injury as well as hepatic inflammation, fibrosis and cancerogenesis. Notably, these combined pathological effects are in part additive but partly even synergistic. And importantly, alcohol does already exhibit synergistic pathological effects with obesity at moderate doses. This indicates significant differences in the dose threshold for hepatotoxic alcohol effects in lean and obese subjects and herewith also has important implications for recommendations for ‘safe' alcohol consumption. The purpose of this brief review is to update the knowledge on the combined effects of alcohol and obesity on the development and progression of liver disease. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important interactive effects of either condition with regard to crucial triggers of liver injury.

Ramaiah S, Rivera C, Arteel G: Early-phase alcoholic liver disease: an update on animal models, pathology, and pathogenesis. Int J Toxicol 2004;23:217-231.
Lieber CS, Schmid R: The effect of ethanol on fatty acid metabolism; stimulation of hepatic fatty acid synthesis in vitro. J Clin Invest 1961;40:394-399.
Galli A, Price D, Crabb D: High-level expression of rat class I alcohol dehydrogenase is sufficient for ethanol-induced fat accumulation in transduced HeLa cells. Hepatology 1999;29:1164-1170.
Clark JM, Brancati FL, Diehl AM: The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960-967.
Rozman D: From nonalcoholic fatty liver disease to hepatocellular carcinoma: a systems understanding. Dig Dis Sci 2014;59:238-241.
Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263-2273.
Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE: Diabetes and apoptosis: lipotoxicity. Apoptosis 2009;14:1484-1495.
Teli MR, James OF, Burt AD, Bennett MK, Day CP: The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995;22:1714-1719.
European Association for the Study of Liver: EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012;57:399-420.
O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology: Alcoholic liver disease. Hepatology 2010;51:307-328.
Mueller S, Millonig G, Seitz HK: Alcoholic liver disease and hepatitis C: a frequently underestimated combination. World J Gastroenterol 2009;15:3462-3471.
Lederer SL, Walters KA, Proll S, Paeper B, Robinzon S, Boix L, et al: Distinct cellular responses differentiating alcohol- and hepatitis C virus-induced liver cirrhosis. Virol J 2006;3:98.
Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, et al: Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29:1215-1219.
Cimino L, Oriani G, D'Arienzo A, Manguso F, Loguercio C, Ascione A, et al: Interactions between metabolic disorders (diabetes, gallstones, and dyslipidaemia) and the progression of chronic hepatitis C virus infection to cirrhosis and hepatocellular carcinoma. A cross-sectional multicentre survey. Dig Liver Dis 2001;33:240-246.
Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ: Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001;21:17-26.
Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112-117.
Ruhl CE, Everhart JE: Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population. Clin Gastroenterol Hepatol 2005;3:1260-1268.
Alatalo PI, Koivisto HM, Hietala JP, Puukka KS, Bloigu R, Niemela OJ: Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index. Am J Clin Nutr 2008;88:1097-1103.
Loomba R, Bettencourt R, Barrett-Connor E: Synergistic association between alcohol intake and body mass index with serum alanine and aspartate aminotransferase levels in older adults: the Rancho Bernardo study. Aliment Pharmacol Ther 2009;30:1137-1149.
Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC: Excess weight risk factor for alcoholic liver disease. Hepatology 1997;25:108-111.
Raynard B, Balian A, Fallik D, Capron F, Bedossa P, Chaput JC, et al: Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 2002;35:635-638.
Ekstedt M, Franzen LE, Holmqvist M, Bendtsen P, Mathiesen UL, Bodemar G, et al: Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2009;44:366-374.
Liu B, Balkwill A, Reeves G, Beral V; Million Women Study Collaborators: Body mass index and risk of liver cirrhosis in middle aged UK women: prospective study. BMJ 2010;340:c912.
Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972-1978.
Loomba R, Yang HI, Su J, Brenner D, Barrett-Connor E, Iloeje U, et al: Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study. Am J Epidemiol 2013;177:333-342.
Carmiel-Haggai M, Cederbaum AI, Nieto N: Binge ethanol exposure increases liver injury in obese rats. Gastroenterology 2003;125:1818-1833.
Xu J, Lai KK, Verlinsky A, Lugea A, French SW, Cooper MP, et al: Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J Hepatol 2011;55:673-682.
Wang Y, Millonig G, Nair J, Patsenker E, Stickel F, Mueller S, et al: Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease. Hepatology 2009;50:453-461.
Purohit V, Gao B, Song BJ: Molecular mechanisms of alcoholic fatty liver. Alcohol Clin Exp Res 2009;33:191-205.
Wang Y, Seitz HK, Wang XD: Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcohol Clin Exp Res 2010;34:567-573.
Gabele E, Dostert K, Dorn C, Patsenker E, Stickel F, Hellerbrand C: A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis. Alcohol Clin Exp Res 2011;35:1361-1367.
Mahli A, Thasler WE, Patsenker E, Muller S, Stickel F, Muller M, et al: Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro. Oncotarget 2015;6:41464-41478.
Wobser H, Dorn C, Weiss TS, Amann T, Bollheimer C, Buttner R, et al: Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res 2009;19:996-1005.
Gebhardt AC, Lucas D, Menez JF, Seitz HK: Chlormethiazole inhibition of cytochrome P450 2E1 as assessed by chlorzoxazone hydroxylation in humans. Hepatology 1997;26:957-961.
Wu D, Wang X, Zhou R, Cederbaum A: CYP2E1 enhances ethanol-induced lipid accumulation but impairs autophagy in HepG2 E47 cells. Biochem Biophys Res Commun 2010;402:116-122.
Swaminathan K, Clemens DL, Dey A: Inhibition of CYP2E1 leads to decreased malondialdehyde-acetaldehyde adduct formation in VL-17A cells under chronic alcohol exposure. Life Sci 2013;92:325-336.
Ding WX, Li M, Chen X, Ni HM, Lin CW, Gao W, et al: Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology 2010;139:1740-1752.
Lin CW, Zhang H, Li M, Xiong X, Chen X, Chen X, et al: Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol 2013;58:993-999.
Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, et al: Autophagy regulates lipid metabolism. Nature 2009;458:1131-1135.
Czaja MJ: Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications. Am J Physiol Cell Physiol 2010;298:C973-C978.
Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, et al: Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis 2014;5:e1179.
Sookoian S, Castano GO, Pirola CJ: Modest alcohol consumption decreases the risk of non-alcoholic fatty liver disease: a meta-analysis of 43 175 individuals. Gut 2014;63:530-532.
Dunn W, Sanyal AJ, Brunt EM, Unalp-Arida A, Donohue M, McCullough AJ, et al: Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol 2012;57:384-391.
Wannamethee SG, Camargo CA Jr, Manson JE, Willett WC, Rimm EB: Alcohol drinking patterns and risk of type 2 diabetes mellitus among younger women. Arch Intern Med 2003;163:1329-1336.
Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, Taniguchi H, et al: Alcohol consumption appears to protect against non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011;33:378-388.
Gunji T, Matsuhashi N, Sato H, Fujibayashi K, Okumura M, Sasabe N, et al: Light and moderate alcohol consumption significantly reduces the prevalence of fatty liver in the Japanese male population. Am J Gastroenterol 2009;104:2189-2195.
Dunn W, Xu R, Schwimmer JB: Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology 2008;47:1947-1954.
Seitz HK: Alcohol and breast cancer. Breast 2012;21:426-427.
Homann N, Konig IR, Marks M, Benesova M, Stickel F, Millonig G, et al: Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C polymorphism. Alcohol Clin Exp Res 2009;33:551-556.
Hellerbrand C: Pathophysiological similarities and synergisms in alcoholic and non-alcoholic steatohepatitis. Dig Dis 2010;28:783-791.
Yan AW, Schnabl B: Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver disease. World J Hepatol 2012;4:110-118.
Szabo G: Gut-liver axis in alcoholic liver disease. Gastroenterology 2015;148:30-36.
Finelli C, Tarantino G: What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 2013;19:802-812.
Rogers CQ, Ajmo JM, You M: Adiponectin and alcoholic fatty liver disease. IUBMB Life 2008;60:790-797.
Wang Y, Zhou M, Lam KS, Xu A: Protective roles of adiponectin in obesity-related fatty liver diseases: mechanisms and therapeutic implications. Arq Bras Endocrinol Metabol 2009;53:201-212.
Rajkovic N, Zamaklar M, Lalic K, Jotic A, Lukic L, Milicic T, et al: Relationship between obesity, adipocytokines and inflammatory markers in type 2 diabetes: relevance for cardiovascular risk prevention. Int J Environ Res Public Health 2014;11:4049-4065.
Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, et al: Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. FASEB J 2004;18:1612-1614.
Nanji AA, French SW: Relationship between pork consumption and cirrhosis. Lancet 1985;1:681-683.
Nanji AA, Mendenhall CL, French SW: Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Exp Res 1989;13:15-19.
Buettner R, Parhofer KG, Woenckhaus M, Wrede CE, Kunz-Schughart LA, Scholmerich J, et al: Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J Mol Endocrinol 2006;36:485-501.
Tipoe GL, Ho CT, Liong EC, Leung TM, Lau TY, Fung ML, et al: Voluntary oral feeding of rats not requiring a very high fat diet is a clinically relevant animal model of non-alcoholic fatty liver disease (NAFLD). Histol Histopathol 2009;24:1161-1169.
Gentile CL, Pagliassotti MJ: The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem 2008;19:567-576.
Wang D, Wei Y, Pagliassotti MJ: Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006;147:943-951.
Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, et al: Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 2008;48:983-992.
Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ: Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 2003;39:978-983.
Bergheim I, Parlesak A, Dierks C, Bode JC, Bode C: Nutritional deficiencies in German middle-class male alcohol consumers: relation to dietary intake and severity of liver disease. Eur J Clin Nutr 2003;57:431-438.
Hansel B, Roussel R, Diguet V, Deplaude A, Chapman MJ, Bruckert E: Relationships between consumption of alcoholic beverages and healthy foods: the French supermarket cohort of 196,000 subjects. Eur J Prev Cardiol 2015;22:215-222.
Chen S, Teoh NC, Chitturi S, Farrell GC: Coffee and non-alcoholic fatty liver disease: brewing evidence for hepatoprotection? J Gastroenterol Hepatol 2014;29:435-441.
Liu F, Wang X, Wu G, Chen L, Hu P, Ren H, et al: Coffee consumption decreases risks for hepatic fibrosis and cirrhosis: a meta-analysis. PLoS One 2015;10:e0142457.
Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, et al: Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 2008;22:811-816.
Becker U, Gronbaek M, Johansen D, Sorensen TI: Lower risk for alcohol-induced cirrhosis in wine drinkers. Hepatology 2002;35:868-875.
Baur JA, Sinclair DA: Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006;5:493-506.
Kasdallah-Grissa A, Mornagui B, Aouani E, Hammami M, Gharbi N, Kamoun A, et al: Protective effect of resveratrol on ethanol-induced lipid peroxidation in rats. Alcohol Alcohol 2006;41:236-239.
Bujanda L, Garcia-Barcina M, Gutierrez-de Juan V, Bidaurrazaga J, de Luco MF, Gutierrez-Stampa M, et al: Effect of resveratrol on alcohol-induced mortality and liver lesions in mice. BMC Gastroenterol 2006;6:35.
Ajmo JM, Liang X, Rogers CQ, Pennock B, You M: Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2008;295:G833-G842.
Kanuri G, Wagnerberger S, Landmann M, Prigl E, Hellerbrand C, Bischoff SC, et al: Effect of acute beer ingestion on the liver: studies in female mice. Eur J Nutr 2015;54:465-474.
Weiskirchen R, Mahli A, Weiskirchen S, Hellerbrand C: The hop constituent xanthohumol exhibits hepatoprotective effects and inhibits the activation of hepatic stellate cells at different levels. Front Physiol 2015;6:140.
Obara K, Mizutani M, Hitomi Y, Yajima H, Kondo K: Isohumulones, the bitter component of beer, improve hyperglycemia and decrease body fat in Japanese subjects with prediabetes. Clin Nutr 2009;28:278-284.
Heyerick A, Zhao Y, Sandra P, Huvaere K, Roelens F, De Keukeleire D: Photolysis of hop-derived trans-iso-alpha-acids and trans-tetrahydroiso-alpha-acids: product identification in relation to the lightstruck flavour of beer. Photochem Photobiol Sci 2003;2:306-314.
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