1932

Abstract

At-risk alcohol use is a major contributor to the global health care burden and leads to preventable deaths and diseases including alcohol addiction, alcoholic liver disease, cardiovascular disease, diabetes, traumatic injuries, gastrointestinal diseases, cancers, and fetal alcohol syndrome. Excessive and frequent alcohol consumption has increasingly been linked to alcohol-associated tissue injury and pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal and in vitro models has elucidated the salient mechanisms involved in alcohol-induced tissue and organ injury. In some cases, these pathophysiological mechanisms are shared across organ systems. The major alcohol- and alcohol metabolite–mediated mechanisms include oxidative stress, inflammation and immunometabolic dysregulation, gut leak and dysbiosis, cell death, extracellular matrix remodeling, endoplasmic reticulum stress, mitochondrial dysfunction, and epigenomic modifications. These mechanisms are complex and interrelated, and determining the interplay among them will make it possible to identify how they synergistically or additively interact to cause alcohol-mediated multiorgan injury. In this article, we review the current understanding of pathophysiological mechanisms involved in alcohol-induced tissue injury.

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2022-02-10
2024-06-19
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Literature Cited

  1. 1. 
    World Health Organ 2018. Alcohol Fact Sheet, World Health Organ. Geneva: https://www.who.int/news-room/fact-sheets/detail/alcohol
    [Google Scholar]
  2. 2. 
    Kranzler HR, Soyka M. 2018. Diagnosis and pharmacotherapy of alcohol use disorder: a review. JAMA 320:815–24
    [Google Scholar]
  3. 3. 
    Poznyak P, Rekve D. 2018. Global Status Report on Alcohol and Health 2018 Geneva: World Health Organ. https://www.who.int/publications/i/item/9789241565639
    [Google Scholar]
  4. 4. 
    NIH (Natl. Inst. Health) 2021. What is a standard drink? Fact Sheet, NIH Bethesda, MD: http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/what-standard-drink
    [Google Scholar]
  5. 5. 
    Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MB, Iacoviello L, de Gaetano G. 2006. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. JAMA Int. Med. 166:2437–45
    [Google Scholar]
  6. 6. 
    Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. 2019. Alcohol use disorders. Lancet 394:781–92
    [Google Scholar]
  7. 7. 
    Peacock A, Leung J, Larney S, Colledge S, Hickman M et al. 2018. Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction 113:1905–26
    [Google Scholar]
  8. 8. 
    van Boekel LC, Brouwers EP, van Weeghel J, Garretsen HF. 2013. Stigma among health professionals towards patients with substance use disorders and its consequences for healthcare delivery: systematic review. Drug Alcohol Depend 131:23–35
    [Google Scholar]
  9. 9. 
    Schomerus G, Matschinger H, Angermeyer MC. 2014. Attitudes towards alcohol dependence and affected individuals: persistence of negative stereotypes and illness beliefs between 1990 and 2011. Eur. Addict. Res. 20:293–99
    [Google Scholar]
  10. 10. 
    Khaderi SA. 2019. Introduction: alcohol and alcoholism. Clin. Liver Dis. 23:1–10
    [Google Scholar]
  11. 11. 
    Wackernah RC, Minnick MJ, Clapp P. 2014. Alcohol use disorder: pathophysiology, effects, and pharmacologic options for treatment. Subst. Abuse Rehabil. 5:1–12
    [Google Scholar]
  12. 12. 
    Gately I. 2009. Drink: A Cultural History of Alcohol New York: Gotham:
    [Google Scholar]
  13. 13. 
    Alcohol Res. Ed. Staff 2018. Drinking patterns and their definitions. Alcohol Res. 39:17–18
    [Google Scholar]
  14. 14. 
    Cook JL, Green CR, Lilley CM, Anderson SM, Baldwin ME et al. 2016. Fetal alcohol spectrum disorder: a guideline for diagnosis across the lifespan. CMAJ 188:191–97
    [Google Scholar]
  15. 15. 
    Dawson DA, Goldstein RB, Chou SP, Ruan WJ, Grant BF. 2008. Age at first drink and the first incidence of adult-onset DSM-IV alcohol use disorders. Alcohol. Clin. Exp. Res. 32:2149–60
    [Google Scholar]
  16. 16. 
    Patrick ME, Evans-Polce R, Kloska DD, Maggs JL, Lanza ST. 2017. Age-related changes in associations between reasons for alcohol use and high-intensity drinking across young adulthood. J. Stud. Alcohol Drugs 78:558–70
    [Google Scholar]
  17. 17. 
    Schmidt NB, Buckner JD, Keough ME. 2007. Anxiety sensitivity as a prospective predictor of alcohol use disorders. Behav. Modif. 31:202–19
    [Google Scholar]
  18. 18. 
    Kuerbis A, Sacco P, Blazer DG, Moore AA. 2014. Substance abuse among older adults. Clin. Geriatr. Med. 30:629–54
    [Google Scholar]
  19. 19. 
    Sawabe M, Saito M, Naka M, Kasahara I, Saito Y et al. 2006. Standard organ weights among elderly Japanese who died in hospital, including 50 centenarians. Pathol. Int. 56:315–23
    [Google Scholar]
  20. 20. 
    Meier P, Seitz HK. 2008. Age, alcohol metabolism and liver disease. Curr. Opin. Clin. Nutr. Metab. Care 11:21–26
    [Google Scholar]
  21. 21. 
    Cederbaum AI. 2012. Alcohol metabolism. Clin. Liver Dis. 16:667–85
    [Google Scholar]
  22. 22. 
    NIAAA (Natl. Inst. Alcohol Abuse Alcohol.) 2021. Alcohol's effects on health Fact Sheet, NIAAA Rockville, MD: https://www.niaaa.nih.gov/alcohols-effects-health/special-populations-co-occurring-disorders/older-adults
    [Google Scholar]
  23. 23. 
    Perkins AE, Varlinskaya EI, Deak T. 2019. From adolescence to late aging: a comprehensive review of social behavior, alcohol, and neuroinflammation across the lifespan. Int. Rev. Neurobiol. 148:231–303
    [Google Scholar]
  24. 24. 
    Meisel SN, Colder CR, Bowker JC, Hussong AM. 2018. A longitudinal examination of mediational pathways linking chronic victimization and exclusion to adolescent alcohol use. Dev. Psychol. 54:1795–807
    [Google Scholar]
  25. 25. 
    Sacco P, Burruss K, Smith CA, Kuerbis A, Harrington D et al. 2015. Drinking behavior among older adults at a continuing care retirement community: affective and motivational influences. Aging Ment. Health 19:279–89
    [Google Scholar]
  26. 26. 
    Mackintosh MA, Earleywine M, Dunn ME 2006. Alcohol expectancies for social facilitation: a short form with decreased bias. Addict. Behav. 31:1536–46
    [Google Scholar]
  27. 27. 
    Kelly S, Olanrewaju O, Cowan A, Brayne C, Lafortune L. 2018. Alcohol and older people: a systematic review of barriers, facilitators and context of drinking in older people and implications for intervention design. PLOS ONE 13:e0191189
    [Google Scholar]
  28. 28. 
    Rehm J, Room R, Monteiro M, Gmel G, Graham K et al. 2003. Alcohol as a risk factor for global burden of disease. Eur. Addict. Res. 9:157–64
    [Google Scholar]
  29. 29. 
    GBD 2016 Alcohol Collab 2018. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 392:1015–35
    [Google Scholar]
  30. 30. 
    McClain C, Vatsalya V, Cave M. 2017. Role of zinc in the development/progression of alcoholic liver disease. Curr. Treat. Options Gastroenterol. 15:285–95
    [Google Scholar]
  31. 31. 
    Zakhari S. 2006. Overview: How is alcohol metabolized by the body?. Alcohol Res. Health 29:245–54
    [Google Scholar]
  32. 32. 
    Lluis JM, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. 2003. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology 124:708–24
    [Google Scholar]
  33. 33. 
    Molina PE, Gardner JD, Souza-Smith FM, Whitaker AM. 2014. Alcohol abuse: critical pathophysiological processes and contribution to disease burden. Physiology 29:203–15
    [Google Scholar]
  34. 34. 
    NIAAA (Natl. Inst. Alcohol Abuse Alcohol.) 2007. Alcohol metabolism: an update Rep. 72 NIAAA Rockville, MD: https://pubs.niaaa.nih.gov/publications/aa72/aa72.htm
    [Google Scholar]
  35. 35. 
    Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G et al. 2001. Gender differences in pharmacokinetics of alcohol. Alcohol. Clin. Exp. Res. 25:502–7
    [Google Scholar]
  36. 36. 
    Cowan JM Jr., Weathermon A, McCutcheon JR, Oliver RD. 1996. Determination of volume of distribution for ethanol in male and female subjects. J. Anal. Toxicol. 20:287–90
    [Google Scholar]
  37. 37. 
    Hernández-Muñoz R, Caballeria J, Baraona E, Uppal R, Greenstein R, Lieber CS 1990. Human gastric alcohol dehydrogenase: its inhibition by H2-receptor antagonists, and its effect on the bioavailability of ethanol. Alcohol. Clin. Exp. Res. 14:946–50
    [Google Scholar]
  38. 38. 
    Jornvall H, Hoog JO. 1995. Nomenclature of alcohol dehydrogenases. Alcohol Alcohol. 30:153–61
    [Google Scholar]
  39. 39. 
    Peng GS, Yin JH, Wang MF, Lee JT, Hsu YD, Yin SJ. 2002. Alcohol sensitivity in Taiwanese men with different alcohol and aldehyde dehydrogenase genotypes. J. Formos. Med. Assoc. 101:769–74
    [Google Scholar]
  40. 40. 
    Luczak SE, Glatt SJ, Wall TL. 2006. Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians. Psychol. Bull. 132:607–21
    [Google Scholar]
  41. 41. 
    Whitfield JB. 2002. Alcohol dehydrogenase and alcohol dependence: variation in genotype-associated risk between populations. Am. J. Hum. Genet. 71:1247–50; author reply 1250–51
    [Google Scholar]
  42. 42. 
    Wall TL, Carr LG, Ehlers CL. 2003. Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in Native American Mission Indians. Am. J. Psychiatry 160:41–46
    [Google Scholar]
  43. 43. 
    Heier C, Xie H, Zimmermann R. 2016. Nonoxidative ethanol metabolism in humans—from biomarkers to bioactive lipids. IUBMB Life 68:916–23
    [Google Scholar]
  44. 44. 
    Criddle DN, Raraty MG, Neoptolemos JP, Tepikin AV, Petersen OH, Sutton R. 2004. Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. PNAS 101:10738–43
    [Google Scholar]
  45. 45. 
    Simon TW. 2018. Providing context for phosphatidylethanol as a biomarker of alcohol consumption with a pharmacokinetic model. Regul. Toxicol. Pharmacol. 94:163–71
    [Google Scholar]
  46. 46. 
    Avila MA, Dufour JF, Gerbes AL, Zoulim F, Bataller R et al. 2020. Recent advances in alcohol-related liver disease (ALD): summary of a gut round table meeting. Gut 69:764–80
    [Google Scholar]
  47. 47. 
    Thursz M, Kamath PS, Mathurin P, Szabo G, Shah VH. 2019. Alcohol-related liver disease: areas of consensus, unmet needs and opportunities for further study. J. Hepatol. 70:521–30
    [Google Scholar]
  48. 48. 
    Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A et al. 2018. Alcoholic liver disease. Nat. Rev. Dis. Primers 4:16
    [Google Scholar]
  49. 49. 
    Asrani SK, Mellinger J, Arab JP, Shah VH. 2021. Reducing the global burden of alcohol-associated liver disease: a blueprint for action. Hepatology 73:2039–50
    [Google Scholar]
  50. 50. 
    Osna NA, Donohue TM Jr., Kharbanda KK. 2017. Alcoholic liver disease: pathogenesis and current management. Alcohol. Res. 38:147–61
    [Google Scholar]
  51. 51. 
    O'Shea RS, Dasarathy S, McCullough AJPract. Guid. Comm. Am. Assoc. Study Liver Dis., Pract. Parameters Comm. Am. Coll. Gastroenterol 2010. Alcoholic liver disease. Hepatology 51:307–28
    [Google Scholar]
  52. 52. 
    Steiner JL, Lang CH. 2017. Etiology of alcoholic cardiomyopathy: mitochondria, oxidative stress and apoptosis. Int. J. Biochem. Cell Biol. 89:125–35
    [Google Scholar]
  53. 53. 
    Simon L, Jolley SE, Molina PE. 2017. Alcoholic myopathy: pathophysiologic mechanisms and clinical implications. Alcohol. Res. 38:207–17
    [Google Scholar]
  54. 54. 
    Fairfield B, Schnabl B. 2021. Gut dysbiosis as a driver in alcohol-induced liver injury. JHEP Rep. 3:100220
    [Google Scholar]
  55. 55. 
    Bishehsari F, Magno E, Swanson G, Desai V, Voigt RM et al. 2017. Alcohol and gut-derived inflammation. Alcohol. Res. 38:163–71
    [Google Scholar]
  56. 56. 
    Rasineni K, Srinivasan MP, Balamurugan AN, Kaphalia BS, Wang S et al. 2020. Recent advances in understanding the complexity of alcohol-induced pancreatic dysfunction and pancreatitis development. Biomolecules 10:669
    [Google Scholar]
  57. 57. 
    Rachdaoui N, Sarkar DK. 2017. Pathophysiology of the effects of alcohol abuse on the endocrine system. Alcohol. Res. 38:255–76
    [Google Scholar]
  58. 58. 
    Sureshchandra S, Raus A, Jankeel A, Ligh BJK, Walter NAR et al. 2019. Dose-dependent effects of chronic alcohol drinking on peripheral immune responses. Sci. Rep. 9:7847
    [Google Scholar]
  59. 59. 
    Boule LA, Kovacs EJ. 2017. Alcohol, aging, and innate immunity. J. Leukoc. Biol. 102:41–55
    [Google Scholar]
  60. 60. 
    Halliwell B. 1999. Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic. Res. 31:261–72
    [Google Scholar]
  61. 61. 
    Ambade A, Mandrekar P. 2012. Oxidative stress and inflammation: essential partners in alcoholic liver disease. Int. J. Hepatol. 2012:853175
    [Google Scholar]
  62. 62. 
    Lu Y, Cederbaum AI. 2008. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol. Med. 44:723–38
    [Google Scholar]
  63. 63. 
    Zhang RH, Gao JY, Guo HT, Scott GI, Eason AR et al. 2013. Inhibition of CYP2E1 attenuates chronic alcohol intake–induced myocardial contractile dysfunction and apoptosis. Biochim. Biophys. Acta Mol. Basis Dis. 1832:128–41
    [Google Scholar]
  64. 64. 
    Jin M, Ande A, Kumar A, Kumar S. 2013. Regulation of cytochrome P450 2E1 expression by ethanol: role of oxidative stress–mediated PKC/JNK/SP1 pathway. Cell Death Dis 4:e554
    [Google Scholar]
  65. 65. 
    Zakhari S. 2013. Alcohol metabolism and epigenetics changes. Alcohol. Res. 35:6–16
    [Google Scholar]
  66. 66. 
    Li S, Tan HY, Wang N, Zhang ZJ, Lao L et al. 2015. The role of oxidative stress and antioxidants in liver diseases. Int. J. Mol. Sci. 16:26087–124
    [Google Scholar]
  67. 67. 
    Meroni M, Longo M, Dongiovanni P. 2019. Alcohol or gut microbiota: Who is the guilty?. Int. J. Mol. Sci. 20:4568
    [Google Scholar]
  68. 68. 
    Kamada N, Seo SU, Chen GY, Núñez G 2013. Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 13:321–35
    [Google Scholar]
  69. 69. 
    Lee E, Lee J-E 2021. Impact of drinking alcohol on gut microbiota: recent perspectives on ethanol and alcoholic beverage. Curr. Opin. Food Sci. 37:91–97
    [Google Scholar]
  70. 70. 
    Sarin SK, Pande A, Schnabl B 2019. Microbiome as a therapeutic target in alcohol-related liver disease. J. Hepatol. 70:260–72
    [Google Scholar]
  71. 71. 
    Starkel P, Leclercq S, de Timary P, Schnabl B. 2018. Intestinal dysbiosis and permeability: the yin and yang in alcohol dependence and alcoholic liver disease. Clin. Sci. 132:199–212
    [Google Scholar]
  72. 72. 
    Kirpich IA, Petrosino J, Ajami N, Feng W, Wang Y et al. 2016. Saturated and unsaturated dietary fats differentially modulate ethanol-induced changes in gut microbiome and metabolome in a mouse model of alcoholic liver disease. Am. J. Pathol. 186:765–76
    [Google Scholar]
  73. 73. 
    Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A et al. 2016. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 65:830–39
    [Google Scholar]
  74. 74. 
    Canesso MCC, Lacerda NL, Ferreira CM, Gonçalves JL, Almeida D et al. 2014. Comparing the effects of acute alcohol consumption in germ-free and conventional mice: the role of the gut microbiota. BMC Microbiol 14:240
    [Google Scholar]
  75. 75. 
    Leclercq S, de Timary P, Delzenne NM, Starkel P. 2017. The link between inflammation, bugs, the intestine and the brain in alcohol dependence. Transl. Psychiatry 7:e1048
    [Google Scholar]
  76. 76. 
    Johnson KV, Foster KR 2018. Why does the microbiome affect behaviour?. Nat. Rev. Microbiol. 16:647–55
    [Google Scholar]
  77. 77. 
    Samuelson DR, Shellito JE, Maffei VJ, Tague ED, Campagna SR et al. 2017. Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae. PLOS Pathog 13:e1006426
    [Google Scholar]
  78. 78. 
    Engen PA, Green SJ, Voigt RM, Forsyth CB, Keshavarzian A. 2015. The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota. Alcohol. Res. 37:223–36
    [Google Scholar]
  79. 79. 
    Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E et al. 2017. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 66:1727–38
    [Google Scholar]
  80. 80. 
    Molina PE, Happel KI, Zhang P, Kolls JK, Nelson S. 2010. Focus on: alcohol and the immune system. Alcohol Res. Health 33:97–108
    [Google Scholar]
  81. 81. 
    Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P et al. 2006. Cytokines and alcohol. Alcohol. Clin. Exp. Res. 30:720–30
    [Google Scholar]
  82. 82. 
    Warburg O, Gawehn K, Geissler AW. 1958. Stoffwechsel der weißen Blutzellen [Metabolism of leukocytes]. Z. Naturforsch. B 13:8515–16
    [Google Scholar]
  83. 83. 
    Lercher A, Baazim H, Bergthaler A. 2020. Systemic immunometabolism: challenges and opportunities. Immunity 53:496–509
    [Google Scholar]
  84. 84. 
    Ford SM Jr., Simon Peter L, Berner P, Cook G, Vande Stouwe C et al. 2018. Differential contribution of chronic binge alcohol and antiretroviral therapy to metabolic dysregulation in SIV-infected male macaques. Am. J. Physiol. Endocrinol. Metab. 315:E892–903
    [Google Scholar]
  85. 85. 
    Souza-Smith FM, Ford SM Jr., Simon L, Molina PE. 2017. Repeated binge-like alcohol intoxication: depot-specific adipose tissue immuno-metabolic dysregulation. Shock 48:243–50
    [Google Scholar]
  86. 86. 
    Barr T, Helms C, Grant K, Messaoudi I 2016. Opposing effects of alcohol on the immune system. Prog. Neuropsychopharmacol. Biol. Psychiatry 65:242–51
    [Google Scholar]
  87. 87. 
    Souza-Smith FM, Simon L, Siggins R, Molina PE 2019. Alcohol-induced mesenteric lymphatic permeability: link to immunometabolic modulation of perilymphatic adipose tissue. Int. J. Mol. Sci. 20:4097
    [Google Scholar]
  88. 88. 
    Steiner JL, Lang CH. 2017. Alcohol, adipose tissue and lipid dysregulation. Biomolecules 7:16
    [Google Scholar]
  89. 89. 
    Prasun P, Ginevic I, Oishi K 2021. Mitochondrial dysfunction in nonalcoholic fatty liver disease and alcohol related liver disease. Transl. Gastroenterol. Hepatol. 6:4
    [Google Scholar]
  90. 90. 
    Tapia-Rojas C, Torres AK, Quintanilla RA. 2019. Adolescence binge alcohol consumption induces hippocampal mitochondrial impairment that persists during the adulthood. Neuroscience 406:356–68
    [Google Scholar]
  91. 91. 
    Sadikot RT, Bedi B, Li J, Yeligar SM. 2019. Alcohol-induced mitochondrial DNA damage promotes injurious crosstalk between alveolar epithelial cells and alveolar macrophages. Alcohol 80:65–72
    [Google Scholar]
  92. 92. 
    Duplanty AA, Simon L, Molina PE 2017. Chronic binge alcohol–induced dysregulation of mitochondrial-related genes in skeletal muscle of simian immunodeficiency virus–infected rhesus macaques at end-stage disease. Alcohol Alcohol. 52:298–304
    [Google Scholar]
  93. 93. 
    Nassir F, Ibdah JA. 2014. Role of mitochondria in alcoholic liver disease. World J. Gastroenterol. 20:2136–42
    [Google Scholar]
  94. 94. 
    Tan HK, Yates E, Lilly K, Dhanda AD 2020. Oxidative stress in alcohol-related liver disease. World J. Hepatol. 12:332–49
    [Google Scholar]
  95. 95. 
    Simon L, Hollenbach AD, Zabaleta J, Molina PE. 2015. Chronic binge alcohol administration dysregulates global regulatory gene networks associated with skeletal muscle wasting in simian immunodeficiency virus–infected macaques. BMC Genom. 16:1097
    [Google Scholar]
  96. 96. 
    Duplanty AA, Siggins RW, Allerton T, Simon L, Molina PE 2018. Myoblast mitochondrial respiration is decreased in chronic binge alcohol administered simian immunodeficiency virus–infected antiretroviral-treated rhesus macaques. Physiol. Rep. 6:e13625
    [Google Scholar]
  97. 97. 
    Han D, Ybanez MD, Johnson HS, McDonald JN, Mesropyan L et al. 2012. Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations. J. Biol. Chem. 287:42165–79
    [Google Scholar]
  98. 98. 
    Morris NL, Harris FL, Brown LAS, Yeligar SM. 2021. Alcohol induces mitochondrial derangements in alveolar macrophages by upregulating NADPH oxidase 4. Alcohol 90:27–38
    [Google Scholar]
  99. 99. 
    Miyata T, Nagy LE. 2020. Programmed cell death in alcohol-associated liver disease. Clin. Mol. Hepatol. 26:618–25
    [Google Scholar]
  100. 100. 
    Yang BC, Wu SY, Leung PS. 2020. Alcohol ingestion induces pancreatic islet dysfunction and apoptosis via mediation of FGF21 resistance. Ann. Transl. Med. 8:310
    [Google Scholar]
  101. 101. 
    Hajnoczky G, Buzas CJ, Pacher P, Hoek JB, Rubin E. 2005. Alcohol and mitochondria in cardiac apoptosis: mechanisms and visualization. Alcohol. Clin. Exp. Res. 29:693–701
    [Google Scholar]
  102. 102. 
    Bolnick JM, Karana R, Chiang PJ, Kilburn BA, Romero R et al. 2014. Apoptosis of alcohol-exposed human placental cytotrophoblast cells is downstream of intracellular calcium signaling. Alcohol. Clin. Exp. Res. 38:1646–53
    [Google Scholar]
  103. 103. 
    Freund G. 1994. Apoptosis and gene expression: perspectives on alcohol-induced brain damage. Alcohol 11:385–87
    [Google Scholar]
  104. 104. 
    Wang S, Pacher P, De Lisle RC, Huang H, Ding WX. 2016. A mechanistic review of cell death in alcohol-induced liver injury. Alcohol. Clin. Exp. Res. 40:1215–23
    [Google Scholar]
  105. 105. 
    Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. 2013. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773–83
    [Google Scholar]
  106. 106. 
    Ye L, Li S, Liu X, Zhang D, Li L, Jiang Y 2021. CB1R promotes chronic alcohol–induced neuronal necroptosis in mice prefrontal cortex. Alcohol Alcohol. 56:230–39
    [Google Scholar]
  107. 107. 
    Gukovskaya AS, Mareninova OA, Odinokova IV, Sung KF, Lugea A et al. 2006. Cell death in pancreatitis: effects of alcohol. J. Gastroenterol. Hepatol. 21:Suppl. 3S10–13
    [Google Scholar]
  108. 108. 
    Petrasek J, Bala S, Csak T, Lippai D, Kodys K et al. 2012. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J. Clin. Investig. 122:3476–89
    [Google Scholar]
  109. 109. 
    Wang F, Li G, Ning J, Chen L, Xu H et al. 2018. Alcohol accumulation promotes esophagitis via pyroptosis activation. Int. J. Biol. Sci. 14:1245–55
    [Google Scholar]
  110. 110. 
    Williams JA, Ding WX. 2020. Role of autophagy in alcohol and drug-induced liver injury. Food Chem. Toxicol. 136:111075
    [Google Scholar]
  111. 111. 
    Girault V, Gilard V, Marguet F, Lesueur C, Hauchecorne M et al. 2017. Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels. Cell Death Dis 8:e2610
    [Google Scholar]
  112. 112. 
    Peng H, Qin X, Chen S, Ceylan AF, Dong M et al. 2020. Parkin deficiency accentuates chronic alcohol intake–induced tissue injury and autophagy defects in brain, liver and skeletal muscle. Acta Biochim. Biophys. Sin. 52:665–74
    [Google Scholar]
  113. 113. 
    Ji C. 2012. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem. Res. Int. 2012:216450
    [Google Scholar]
  114. 114. 
    Pandol SJ, Gorelick FS, Gerloff A, Lugea A. 2010. Alcohol abuse, endoplasmic reticulum stress and pancreatitis. Dig. Dis. 28:776–82
    [Google Scholar]
  115. 115. 
    Kaphalia L, Boroumand N, Hyunsu J, Kaphalia BS, Calhoun WJ. 2014. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding. Toxicol. Appl. Pharmacol. 277:109–17
    [Google Scholar]
  116. 116. 
    Dolin CE, Arteel GE. 2020. The matrisome, inflammation, and liver disease. Semin. Liver Dis. 40:180–88
    [Google Scholar]
  117. 117. 
    Ninh VK, El Hajj EC, Mouton AJ, Gardner JD 2019. Prenatal alcohol exposure causes adverse cardiac extracellular matrix changes and dysfunction in neonatal mice. Cardiovasc. Toxicol. 19:389–400
    [Google Scholar]
  118. 118. 
    Sueblinvong V, Kerchberger VE, Saghafi R, Mills ST, Fan X, Guidot DM 2014. Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice. Alcohol. Clin. Exp. Res. 38:336–43
    [Google Scholar]
  119. 119. 
    Arteel GE, Naba A. 2020. The liver matrisome—looking beyond collagens. JHEP Rep 2:100115
    [Google Scholar]
  120. 120. 
    Aziz-Seible RS, Casey CA. 2011. Fibronectin: functional character and role in alcoholic liver disease. World J. Gastroenterol. 17:2482–99
    [Google Scholar]
  121. 121. 
    Seth D, Duly A, Kuo PC, McCaughan GW, Haber PS. 2014. Osteopontin is an important mediator of alcoholic liver disease via hepatic stellate cell activation. World J. Gastroenterol. 20:13088–104
    [Google Scholar]
  122. 122. 
    Seth D, D'Souza El-Guindy NB, Apte M, Mari M, Dooley S et al. 2010. Alcohol, signaling, and ECM turnover. Alcohol. Clin. Exp. Res. 34:4–18
    [Google Scholar]
  123. 123. 
    Dodd T, Simon L, LeCapitaine NJ, Zabaleta J, Mussell J et al. 2014. Chronic binge alcohol administration accentuates expression of pro-fibrotic and inflammatory genes in the skeletal muscle of simian immunodeficiency virus–infected macaques. Alcohol. Clin. Exp. Res. 38:2697–706
    [Google Scholar]
  124. 124. 
    Simon L, LeCapitaine N, Berner P, Vande Stouwe C, Mussell JC et al. 2014. Chronic binge alcohol consumption alters myogenic gene expression and reduces in vitro myogenic differentiation potential of myoblasts from rhesus macaques. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306:R837–44
    [Google Scholar]
  125. 125. 
    Lasek AW. 2016. Effects of ethanol on brain extracellular matrix: implications for alcohol use disorder. Alcohol. Clin. Exp. Res. 40:2030–42
    [Google Scholar]
  126. 126. 
    Trindade P, Hampton B, Manhães AC, Medina AE. 2016. Developmental alcohol exposure leads to a persistent change on astrocyte secretome. J. Neurochem. 137:730–43
    [Google Scholar]
  127. 127. 
    Rubio-Araiz A, Porcu F, Pérez-Hernández M, García-Gutiérrez MS, Aracil-Fernández MA et al. 2017. Disruption of blood–brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. Addict. Biol. 22:1103–16
    [Google Scholar]
  128. 128. 
    Go BS, Sirohi S, Walker BM 2020. The role of matrix metalloproteinase-9 in negative reinforcement learning and plasticity in alcohol dependence. Addict. Biol. 25:e12715
    [Google Scholar]
  129. 129. 
    Chen H, Lasek AW 2020. Perineuronal nets in the insula regulate aversion-resistant alcohol drinking. Addict. Biol. 25:e12821
    [Google Scholar]
  130. 130. 
    Coleman LG Jr., Liu W, Oguz I, Styner M, Crews FT. 2014. Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility. Pharmacol. Biochem. Behav. 116:142–51
    [Google Scholar]
  131. 131. 
    Poole LG, Arteel GE. 2016. Transitional remodeling of the hepatic extracellular matrix in alcohol-induced liver injury. Biomed. Res. Int. 2016:3162670
    [Google Scholar]
  132. 132. 
    About I. 2018.. “ The stem cell fashion”: Do we need only stem cells for tissue regeneration?. Clin. Oral Investig. 22:553–54
    [Google Scholar]
  133. 133. 
    Di Rocco G, Baldari S, Pani G, Toietta G 2019. Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells. Cell Mol. Life Sci. 76:231–44
    [Google Scholar]
  134. 134. 
    Michalopoulos GK, Bhushan B. 2021. Liver regeneration: biological and pathological mechanisms and implications. Nat. Rev. Gastroenterol. Hepatol. 18:40–55
    [Google Scholar]
  135. 135. 
    Kuttippurathu L, Juskeviciute E, Dippold RP, Hoek JB, Vadigepalli R. 2016. A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration. BMC Genom. 17:260
    [Google Scholar]
  136. 136. 
    Duguay L, Coutu D, Hetu C, Joly JG. 1982. Inhibition of liver regeneration by chronic alcohol administration. Gut 23:8–13
    [Google Scholar]
  137. 137. 
    Hosseini N, Shor J, Szabo G. 2019. Alcoholic hepatitis: a review. Alcohol Alcohol. 54:408–16
    [Google Scholar]
  138. 138. 
    Levitt DE, Yeh AY, Prendergast MJ, Budnar RG Jr., Adler KA et al. 2020. Chronic alcohol dysregulates skeletal muscle myogenic gene expression after hind limb immobilization in female rats. Biomolecules 10:441
    [Google Scholar]
  139. 139. 
    Adler K, Molina PE, Simon L. 2019. Epigenomic mechanisms of alcohol-induced impaired differentiation of skeletal muscle stem cells: role of class IIA histone deacetylases. Physiol. Genom. 51:471–79
    [Google Scholar]
  140. 140. 
    Simon L, Ford SM Jr., Song K, Berner P, Vande Stouwe C et al. 2017. Decreased myoblast differentiation in chronic binge alcohol–administered simian immunodeficiency virus–infected male macaques: role of decreased miR-206. Am. J. Physiol. Regul. Integr. Comp. Physiol. 313:R240–50
    [Google Scholar]
  141. 141. 
    Levitt DE, Chalapati N, Prendergast MJ, Simon L, Molina PE 2020. Ethanol-impaired myogenic differentiation is associated with decreased myoblast glycolytic function. Alcohol. Clin. Exp. Res. 44:2166–76
    [Google Scholar]
  142. 142. 
    Siggins RW, Molina P, Zhang P, Bagby GJ, Nelson S et al. 2014. Dysregulation of myelopoiesis by chronic alcohol administration during early SIV infection of rhesus macaques. Alcohol. Clin. Exp. Res. 38:1993–2000
    [Google Scholar]
  143. 143. 
    Seitz HK, Poschl G. 1997. The role of gastrointestinal factors in alcohol metabolism. Alcohol Alcohol. 32:543–49
    [Google Scholar]
  144. 144. 
    Vincon P, Wunderer J, Simanowski UA, Koll M, Preedy VR et al. 2003. Inhibition of alcohol-associated colonic hyperregeneration by α-tocopherol in the rat. Alcohol. Clin. Exp. Res. 27:100–6
    [Google Scholar]
  145. 145. 
    Simanowski UA, Homann N, Knühl M, Arce L, Waldherr R et al. 2001. Increased rectal cell proliferation following alcohol abuse. Gut 49:418–22
    [Google Scholar]
  146. 146. 
    Simanowski UA, Stickel F, Maier H, Gartner U, Seitz HK. 1995. Effect of alcohol on gastrointestinal cell regeneration as a possible mechanism in alcohol-associated carcinogenesis. Alcohol 12:111–15
    [Google Scholar]
  147. 147. 
    Rodriguez FD. 2021. Targeting epigenetic mechanisms to treat alcohol use disorders (AUD). Curr. Pharm. Des. 27:3252–72
    [Google Scholar]
  148. 148. 
    Pal-Bhadra M, Bhadra U, Jackson DE, Mamatha L, Park PH, Shukla SD. 2007. Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- and down-regulation of genes by ethanol in hepatocytes. Life Sci 81:979–87
    [Google Scholar]
  149. 149. 
    Lin XX, Lian GH, Peng SF, Zhao Q, Xu Y et al. 2018. Reversing epigenetic alterations caused by alcohol: a promising therapeutic direction for alcoholic liver disease. Alcohol. Clin. Exp. Res. 42:1863–73
    [Google Scholar]
  150. 150. 
    Bohnsack JP, Pandey SC. 2021. Histone modifications, DNA methylation, and the epigenetic code of alcohol use disorder. Int. Rev. Neurobiol. 156:1–62
    [Google Scholar]
  151. 151. 
    Sarkar DK. 2016. Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review. Addict. Biol. 21:23–34
    [Google Scholar]
  152. 152. 
    Kaminen-Ahola N. 2020. Fetal alcohol spectrum disorders: genetic and epigenetic mechanisms. Prenat. Diagn. 40:1185–92
    [Google Scholar]
  153. 153. 
    Stephenson M, Bollepalli S, Cazaly E, Salvatore JE, Barr P et al. 2021. Associations of alcohol consumption with epigenome-wide DNA methylation and epigenetic age acceleration: individual-level and co-twin comparison analyses. Alcohol. Clin. Exp. Res. 45:318–28
    [Google Scholar]
  154. 154. 
    Longley MJ, Lee J, Jung J, Lohoff FW 2021. Epigenetics of alcohol use disorder—a review of recent advances in DNA methylation profiling. Addict. Biol. 26:e13006
    [Google Scholar]
  155. 155. 
    Bohnsack JP, Teppen T, Kyzar EJ, Dzitoyeva S, Pandey SC 2019. The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders. Transl. Psychiatry 9:34
    [Google Scholar]
  156. 156. 
    Johnstone AL, Andrade NS, Barbier E, Khomtchouk BB, Rienas CA et al. 2021. Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways. Addict. Biol. 26:e12816
    [Google Scholar]
  157. 157. 
    Wang KS, Liu X, Zhang Q, Wu LY, Zeng M. 2012. Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms. J. Neural. Transm. 119:425–33
    [Google Scholar]
  158. 158. 
    Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD 2012. Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J. Neurosci. 32:1884–97
    [Google Scholar]
  159. 159. 
    Parira T, Laverde A, Agudelo M. 2017. Epigenetic interactions between alcohol and cannabinergic effects: focus on histone modification and DNA methylation. J. Alcohol. Drug Depend. 5:259
    [Google Scholar]
  160. 160. 
    Agudelo M, Figueroa G, Parira T, Yndart A, Muñoz K et al. 2016. Profile of class I histone deacetylases (HDAC) by human dendritic cells after alcohol consumption and in vitro alcohol treatment and their implication in oxidative stress: role of HDAC inhibitors trichostatin A and mocetinostat. PLOS ONE 11:e0156421
    [Google Scholar]
  161. 161. 
    Moonat S, Sakharkar AJ, Zhang H, Tang L, Pandey SC. 2013. Aberrant histone deacetylase 2–mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol. Psychiatry 73:763–73
    [Google Scholar]
  162. 162. 
    Sakharkar AJ, Zhang H, Tang L, Shi G, Pandey SC. 2012. Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. Alcohol. Clin. Exp. Res. 36:61–71
    [Google Scholar]
  163. 163. 
    Torres JL, Novo-Veleiro I, Manzanedo L, Alvela-Suárez L, Macías R et al. 2018. Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease. World J. Gastroenterol. 24:4104–18
    [Google Scholar]
  164. 164. 
    Natarajan SK, Pachunka JM, Mott JL. 2015. Role of microRNAs in alcohol-induced multi-organ injury. Biomolecules 5:3309–38
    [Google Scholar]
  165. 165. 
    Iwagami Y, Zou J, Zhang H, Cao K, Ji C et al. 2018. Alcohol-mediated miR-34a modulates hepatocyte growth and apoptosis. J. Cell Mol. Med. 22:3987–95
    [Google Scholar]
  166. 166. 
    Bala S, Szabo G. 2012. MicroRNA signature in alcoholic liver disease. Int. J. Hepatol. 2012:498232
    [Google Scholar]
  167. 167. 
    Ibáñez F, Ureña-Peralta JR, Costa-Alba P, Torres JL, Laso FJ et al. 2020. Circulating microRNAs in extracellular vesicles as potential biomarkers of alcohol-induced neuroinflammation in adolescence: gender differences. Int. J. Mol. Sci. 21:6730
    [Google Scholar]
  168. 168. 
    Bala S, Petrasek J, Mundkur S, Catalano D, Levin I et al. 2012. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 56:1946–57
    [Google Scholar]
  169. 169. 
    Tang Y, Banan A, Forsyth CB, Fields JZ, Lau CK et al. 2008. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol. Clin. Exp. Res. 32:355–64
    [Google Scholar]
  170. 170. 
    Pan JH, Kim H, Tang J, Beane KE, Park JW et al. 2020. Acute alcohol consumption–induced let-7a inhibition exacerbates hepatic apoptosis by regulating Rb1 in mice. Alcohol 85:13–20
    [Google Scholar]
  171. 171. 
    Banales JM, Feldstein AE, Sanger H, Lukacs-Kornek V, Szabo G, Kornek M. 2019. Extracellular vesicles in liver diseases: meeting report from the International Liver Congress 2018. Hepatol. Commun. 3:305–15
    [Google Scholar]
  172. 172. 
    Verma VK, Li H, Wang R, Hirsova P, Mushref M et al. 2016. Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J. Hepatol. 64:651–60
    [Google Scholar]
  173. 173. 
    Momen-Heravi F, Bala S, Kodys K, Szabo G 2015. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci. Rep. 5:9991
    [Google Scholar]
  174. 174. 
    Eguchi A, Lazaro RG, Wang J, Kim J, Povero D et al. 2017. Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a microRNA barcode that can be detected in blood. Hepatology 65:475–90
    [Google Scholar]
  175. 175. 
    Saha B, Momen-Heravi F, Kodys K, Szabo G 2016. MicroRNA cargo of extracellular vesicles from alcohol-exposed monocytes signals naive monocytes to differentiate into M2 macrophages. J. Biol. Chem. 291:149–59
    [Google Scholar]
  176. 176. 
    Tseng AM, Chung DD, Pinson MR, Salem NA, Eaves SE, Miranda RC. 2019. Ethanol exposure increases miR-140 in extracellular vesicles: implications for fetal neural stem cell proliferation and maturation. Alcohol. Clin. Exp. Res. 43:1414–26
    [Google Scholar]
  177. 177. 
    Lamas-Paz A, Morán L, Peng J, Salinas B, López-Alcantara N et al. 2020. Intestinal epithelial cell-derived extracellular vesicles modulate hepatic injury via the gut–liver axis during acute alcohol injury. Front. Pharmacol. 11:603771
    [Google Scholar]
  178. 178. 
    Tavanasefat H, Li F, Koyano K, Gourtani BK, Marty V et al. 2020. Molecular consequences of fetal alcohol exposure on amniotic exosomal miRNAs with functional implications for stem cell potency and differentiation. PLOS ONE 15:e0242276
    [Google Scholar]
  179. 179. 
    Tulisiak CT, Harris RA, Ponomarev I. 2017. DNA modifications in models of alcohol use disorders. Alcohol 60:19–30
    [Google Scholar]
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