Animal models of alcoholic liver disease: Pathogenesis and clinical relevance

Gene Expression

Volumn 17, Issue 3, 2017, Pages 173-186

  Gao, Bin ^a   Xu, Ming Jiang ^a   Bertola, Adeline ^a,b   Wang, Hua ^a,c   Zhou, Zhou ^a   Liangpunsakul, Suthat ^d,e  

^a NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM   (United States)

^b UNIVERSITÉ CÔTE D'AZUR   (France)

^c ANHUI MEDICAL UNIVERSITY   (China)

^d INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e RICHARD L ROUDEBUSH VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Alcoholic liver disease (ALD); Animal models; Inflammation and injury; Liver diseases; Miscellaneous metabolic liver diseases; Molecular basis

Indexed keywords

ALCOHOL; SIRTUIN 1; FAT-SPECIFIC PROTEIN 27, MOUSE; PROTEIN; SIRT1 PROTEIN, MOUSE;

ALCOHOL CONSUMPTION; ALCOHOL LIVER DISEASE; AUTOPHAGY; BINGE DRINKING; CELL DEATH; ENVIRONMENT; GENETIC BACKGROUND; KUPFFER CELL; LIPID DIET; LIVER INJURY; MACROPHAGE; NATURAL KILLER T CELL; NEUTROPHIL CHEMOTAXIS; NONHUMAN; OBESITY; PATHOGENESIS; REVIEW; ALCOHOLISM; ANIMAL; C57BL MOUSE; COMPLICATION; CYTOLOGY; DISEASE MODEL; DRINKING BEHAVIOR; FEMALE; GENETICS; HUMAN; INFLAMMATION; MALE; METABOLISM; MOUSE; NEUTROPHIL; PATHOPHYSIOLOGY;

ALCOHOL DRINKING; ALCOHOLISM; ANIMALS; BINGE DRINKING; DIET, HIGH-FAT; DISEASE MODELS, ANIMAL; FEMALE; HUMANS; INFLAMMATION; KUPFFER CELLS; LIVER DISEASES, ALCOHOLIC; MACROPHAGES; MALE; MICE; MICE, INBRED C57BL; NATURAL KILLER T-CELLS; NEUTROPHILS; OBESITY; OVERWEIGHT; PROTEINS; SIRTUIN 1;

EID: 85021999399     PISSN: 10522166     EISSN: None     Source Type: Journal    
DOI: 10.3727/105221617X695519     Document Type: Review

References (104)

1. Gao B, Bataller R. Alcoholic liver disease: Pathogenesis and new therapeutic targets. Gastroenterology 2011;141: 1572-85.
2. Younossi Z, Henry L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liverrelated morbidity and mortality. Gastroenterology 2016; 150:1778-85.
3. Liangpunsakul S, Haber P, McCaughan GW. Alcoholic liver disease in Asia, Europe, and North America. Gastroenterology 2016;150:1786-97.
4. Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: Translational approaches to develop targeted therapies. Hepatology 2016;64:1343-55.
5. Wilkin RJ, Lalor PF, Parker R, Newsome PN. Murine models of acute alcoholic hepatitis and their relevance to human disease. Am J Pathol. 2016;186:748-60.
6. Askgaard G, Gronbaek M, Kjaer MS, Tjonneland A, Tolstrup JS. Alcohol drinking pattern and risk of alcoholic liver cirrhosis: A prospective cohort study. J Hepatol. 2015;62:1061-7.
7. 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;88:1097-103.
8. Shen Z, Li Y, Yu C, Shen Y, Xu L, Xu C, Xu G. A cohort study of the effect of alcohol consumption and obesity on serum liver enzyme levels. Eur J Gastroenterol Hepatol. 2010;22:820-5.
9. 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;30:1137-49.
10. Liangpunsakul S, Puri P, Shah VH, Kamath P, Sanyal A, Urban T, Ren X, Katz B, Radaeva S, Chalasani N, Crabb DW, Translational Research and Evolving Alcoholic Hepatitis Treatment Consortium. Effects of age, sex, body weight, and quantity of alcohol consumption on occurrence and severity of alcoholic hepatitis. Clin Gastroenterol Hepatol. 2016;14:1831-8.e3.
11. Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, Gao B. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: Role of signal transducer and activator of transcription 3. Hepatology 2010;52:1291-300.
12. Bertola A, Mathews S, Ki SH, Wang H, Gao B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc. 2013;8:627-37.
13. Matyas C, Varga ZV, Mukhopadhyay P, Paloczi J, Lajtos T, Erdelyi K, Nemeth BT, Nan M, Hasko G, Gao B, Pacher P. Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis. Am J Physiol Heart Circ Physiol. 2016;310:H1658-70.
14. Ren Z, Yang F, Wang X, Wang Y, Xu M, Frank JA, Ke ZJ, Zhang Z, Shi X, Luo J. Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation. Toxicol Appl Pharmacol. 2016;308:11-9.
15. Fulham MA, Mandrekar P. Sexual dimorphism in alcohol induced adipose inflammation relates to liver injury. PLoS One 2016;11:e0164225.
16. Aroor AR, Restrepo RJ, Kharbanda KK, Shukla SD. Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury. Hepatol Int. 2014;8(Suppl 2):421-30.
17. Zabala V, Tong M, Yu R, Ramirez T, Yalcin EB, Balbo S, Silbermann E, Deochand C, Nunez K, Hecht S, de la Monte SM. Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease. Alcohol Alcohol. 2015; 50:118-31.
18. Chang B, Xu MJ, Zhou Z, Cai Y, Li M, Wang W, Feng D, Bertola A, Wang H, Kunos G, Gao B. Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: An important role for CXCL1. Hepatology 2015;62:1070-85.
19. Lazaro R, Wu R, Lee S, Zhu NL, Chen CL, French SW, Xu J, Machida K, Tsukamoto H. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 2015;61:129-40.
20. Ueno A, Lazaro R, Wang PY, Higashiyama R, Machida K, Tsukamoto H. Mouse intragastric infusion (iG) model. Nat Protoc. 2012;7:771-81.
21. Xu MJ, Cai Y, Wang H, Altamirano J, Chang B, Bertola A, Odena G, Lu J, Tanaka N, Matsusue K, Matsubara T, Mukhopadhyay P, Kimura S, Pacher P, Gonzalez FJ, Bataller R, Gao B. Fat-specific protein 27/CIDEC promotes development of alcoholic steatohepatitis in mice and humans. Gastroenterology 2015;149:1030-41.e6.
22. Belknap JK, Crabbe JC, Young ER. Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology (Berl) 1993;112:503-10.
23. Iimuro Y, Frankenberg MV, Arteel GE, Bradford BU, Wall CA, Thurman RG. Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males. Am J Physiol. 1997;272:G1186-94.
24. Li M, He Y, Zhou Z, Ramirez T, Gao Y, Gao Y, Ross RA, Cao H, Cai Y, Xu M, Feng D, Zhang P, Liangpunsakul S, Gao B. MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils. Gut 2017;66:705-15.
25. Mukhopadhyay P, Horvath B, Rajesh M, Varga ZV, Gariani K, Ryu D, Cao Z, Holovac E, Park O, Zhou Z, Xu MJ, Wang W, Godlewski G, Paloczi J, Nemeth BT, Persidsky Y, Liaudet L, Hasko G, Bai P, Hamid Boulares A, Auwerx J, Gao B, Pacher P. PARP inhibition protects against alcoholic and nonalcoholic steatohepatitis. J Hepatol. 2017;663:589-600.
26. Xu J, Lai KK, Verlinsky A, Lugea A, French SW, Cooper MP, Ji C, Tsukamoto H. Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J Hepatol. 2011;55:673-82.
27. You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 2005;42:568-77.
28. Gao B, Tsukamoto H. Inflammation in alcoholic and nonalcoholic fatty liver disease: Friend or foe? Gastroenterology 2016;150:1704-9.
29. Bertola A, Park O, Gao B. Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: A critical role for E-selectin. Hepatology 2013;58:1814-23.
30. Wieser V, Adolph TE, Enrich B, Kuliopulos A, Kaser A, Tilg H, Kaneider NC. Reversal of murine alcoholic steatohepatitis by pepducin-based functional blockade of interleukin-8 receptors. Gut 2017;66:930-8.
31. Roh YS, Zhang B, Loomba R, Seki E. TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration. Am J Physiol Gastrointest Liver Physiol. 2015;309:G30-41.
32. Cai Y, Jogasuria A, Yin H, Xu MJ, Hu X, Wang J, Kim C, Wu J, Lee K, Gao B, You M. The detrimental role played by lipocalin-2 in alcoholic fatty liver in mice. Am J Pathol. 2016;186:2417-28.
33. Wieser V, Tymoszuk P, Adolph TE, Grander C, Grabherr F, Enrich B, Pfister A, Lichtmanegger L, Gerner R, Drach M, Moser P, Zoller H, Weiss G, Moschen AR, Theurl I, Tilg H. Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease. J Hepatol. 2016;64:872-80.
34. Morales-Ibanez O, Dominguez M, Ki SH, Marcos M, Chaves JF, Nguyen-Khac E, Houchi H, Affo S, Sancho- Bru P, Altamirano J, Michelena J, Garcia-Pagan JC, Abraldes JG, Arroyo V, Caballeria J, Laso FJ, Gao B, Bataller R. Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. Hepatology 2013;58:1742-56.
35. Ge X, Leung TM, Arriazu E, Lu Y, Urtasun R, Christensen B, Fiel MI, Mochida S, Sorensen ES, Nieto N. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factoralpha and prevents early alcohol-induced liver injury in mice. Hepatology 2014;59:1600-16.
36. Coombes JD, Syn WK. Differential osteopontin functions: The role of osteopontin isoforms. Hepatology 2015; 62:323-4.
37. Gantier MP. The not-so-neutral role of microRNAs in neutrophil biology. J Leukoc Biol. 2013;94:575-83.
38. Wang S, Ding WX. A small RNA in neutrophils protects against acute-on-chronic alcoholic liver injury. Gut 2017;66:565-6.
39. Das S, Maras JS, Hussain MS, Sharma S, David P, Sukriti S, Shasthry SM, Maiwall R, Trehanpati N, Singh TP, Sarin SK. Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis. Hepatology 2017;65:631-46.
40. Markwick LJ, Riva A, Ryan JM, Cooksley H, Palma E, Tranah TH, Manakkat Vijay GK, Vergis N, Thursz M, Evans A, Wright G, Tarff S, O'Grady J, Williams R, Shawcross DL, Chokshi S. Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis. Gastroenterology 2015;148:590-602.e10.
41. Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, Augustin S, Mookerjee RP, Michelena J, Smyrk TC, Buob D, Leteurtre E, Rincon D, Ruiz P, Garcia-Pagan JC, Guerrero-Marquez C, Jones PD, Barritt ASt, Arroyo V, Bruguera M, Banares R, Gines P, Caballeria J, Roskams T, Nevens F, Jalan R, Mathurin P, Shah VH, Bataller R. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146:1231-9.e1-6.
42. Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: From pathogenesis to novel therapeutic strategies. Cell Mol Immunol. 2016;13:316-27.
43. Cui K, Yan G, Xu C, Chen Y, Wang J, Zhou R, Bai L, Lian Z, Wei H, Sun R, Tian Z. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1beta in mice. J Hepatol. 2015;62:1311-8.
44. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: Immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009;86:513-28.
45. Bandyopadhyay K, Marrero I, Kumar V. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol. 2016;13:337-46.
46. Mathews S, Feng D, Maricic I, Ju C, Kumar V, Gao B. Invariant natural killer T cells contribute to chronic-plusbinge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration. Cell Mol Immunol. 2016;13:206-16.
47. Maricic I, Sheng H, Marrero I, Seki E, Kisseleva T, Chaturvedi S, Molle N, Mathews SA, Gao B, Kumar V. Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology 2015;61:1357-69.
48. Nagy LE, Ding WX, Cresci G, Saikia P, Shah VH. Linking pathogenic mechanisms of alcoholic liver disease with clinical phenotypes. Gastroenterology 2016;150:1756-68.
49. Zhou H, Yu M, Zhao J, Martin BN, Roychowdhury S, McMullen MR, Wang E, Fox PL, Yamasaki S, Nagy LE, Li X. IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease. Hepatology 2016;64:1978-93.
50. Roychowdhury S, McCullough RL, Sanz-Garcia C, Saikia P, Alkhouri N, Matloob A, Pollard KA, McMullen MR, Croniger CM, Nagy LE. Receptor interacting protein 3 protects mice from high-fat diet-induced liver injury. Hepatology 2016;64:1518-33.
51. Bukong TN, Iracheta-Vellve A, Saha B, Ambade A, Satishchandran A, Gyongyosi B, Lowe P, Catalano D, Kodys K, Szabo G. Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease. Hepatology 2016;64: 1057-71.
52. Wang S, Pacher P, De Lisle RC, Huang H, Ding WX. A mechanistic review of cell death in alcohol-induced liver injury. Alcohol Clin Exp Res. 2016;40:1215-23.
53. Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 2013; 57:1773-83.
54. Wang S, Ni HM, Dorko K, Kumer SC, Schmitt TM, Nawabi A, Komatsu M, Huang H, Ding WX. Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury. Oncotarget 2016;7:17681-98.
55. Li Y, Wang S, Ni HM, Huang H, Ding WX. Autophagy in alcohol-induced multiorgan injury: Mechanisms and potential therapeutic targets. Biomed Res Int. 2014;2014: 498491.
56. Ding WX, Manley S, Ni HM. The emerging role of autophagy in alcoholic liver disease. Exp Biol Med. (Maywood) 2011;236:546-56.
57. Wang L, Khambu B, Zhang H, Yin XM. Autophagy in alcoholic liver disease, self-eating triggered by drinking. Clin Res Hepatol Gastroenterol. 2015;39(Suppl 1):S2-6.
58. Lin CW, Zhang H, Li M, Xiong X, Chen X, Chen X, Dong XC, Yin XM. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol. 2013;58:993-9.
59. Dolganiuc A, Thomes PG, Ding WX, Lemasters JJ, Donohue TM, Jr. Autophagy in alcohol-induced liver diseases. Alcohol Clin Exp Res. 2012;36:1301-8.
60. Ni HM, Bhakta A, Wang S, Li Z, Manley S, Huang H, Copple B, Ding WX. Role of hypoxia inducing factor- 1beta in alcohol-induced autophagy, steatosis and liver injury in mice. PLoS One 2014;9:e115849.
61. Williams JA, Ni HM, Ding Y, Ding WX. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol. 2015;309:G324-40.
62. Denaes T, Lodder J, Chobert MN, Ruiz I, Pawlotsky JM, Lotersztajn S, Teixeira-Clerc F. The cannabinoid receptor 2 protects against alcoholic liver disease via a macrophage autophagy-dependent pathway. Sci Rep. 2016;6:28806.
63. Xu X, Park JG, So JS, Lee AH. Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis. Hepatology 2015;61:857-69.
64. Langhi C, Baldan A. CIDEC/FSP27 is regulated by peroxisome proliferator-activated receptor alpha and plays a critical role in fasting- and diet-induced hepatosteatosis. Hepatology 2015;61:1227-38.
65. Matsusue K, Kusakabe T, Noguchi T, Takiguchi S, Suzuki T, Yamano S, Gonzalez FJ. Hepatic steatosis in leptin-deficient mice is promoted by the PPARgamma target gene Fsp27. Cell Metab. 2008;7:302-11.
66. Wang W, Xu MJ, Cai Y, Zhou Z, Cao H, Mukhopadhyay P, Pacher P, Zheng S, Gonzalez FJ, Gao B. Inflammation is independent of steatosis in a murine model of steatohepatitis. Hepatology 2017 (Epub ahead of print).
67. Yin H, Hu M, Liang X, Ajmo JM, Li X, Bataller R, Odena G, Stevens SM, Jr., You M. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 2014;146:801-11.
68. Ramirez T, Li YM, Yin S, Xu MJ, Feng D, Zhou Z, Zang M, Mukhopadhyay P, Varga ZV, Pacher P, Gao B, Wang H. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol. 2017;66:601-9.
69. Hu M, Yin H, Mitra MS, Liang X, Ajmo JM, Nadra K, Chrast R, Finck BN, You M. Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice. Hepatology 2013;58:1953-63.
70. Yin H, Liang X, Jogasuria A, Davidson NO, You M. miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling. Am J Pathol. 2015;185:1286-96.
71. Wang J, Kim C, Jogasuria A, Han Y, Hu X, Wu J, Shen H, Chrast R, Finck BN, You M. Myeloid cell-specific lipin-1 deficiency stimulates endocrine adiponectin-FGF15 axis and ameliorates ethanol-induced liver injury in mice. Sci Rep. 2016;6:34117.
72. Potthoff MJ. FGF21 and metabolic disease in 2016: A new frontier in FGF21 biology. Nat Rev Endocrinol. 2017;13:74-6.
73. Gong Q, Hu Z, Zhang F, Cui A, Chen X, Jiang H, Gao J, Chen X, Han Y, Liang Q, Ye D, Shi L, Chin YE, Wang Y, Xiao H, Guo F, Liu Y, Zang M, Xu A, Li Y. Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice. Hepatology 2016;64:425-38.
74. Mahlapuu M, Marschall HU. Fibroblast growth factor 21 signaling: The liver in focus. Hepatology 2016;64:333-5.
75. Liu Y, Zhao C, Xiao J, Liu L, Zhang M, Wang C, Wu G, Zheng MH, Xu LM, Chen YP, Mohammadi M, Chen SY, Cave M, McClain C, Li X, Feng W. Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. Sci Rep. 2016;6:31026.
76. Zhao C, Liu Y, Xiao J, Liu L, Chen S, Mohammadi M, McClain CJ, Li X, Feng W. FGF21 mediates alcoholinduced adipose tissue lipolysis by activation of systemic release of catecholamine in mice. J Lipid Res. 2015;56:1481-91.
77. Lounis MA, Escoula Q, Veillette C, Bergeron KF, Ntambi JM, Mounier C. SCD1 deficiency protects mice against ethanol-induced liver injury. Biochim Biophys Acta 2016;1861:1662-70.
78. Xu J, Li Y, Chen WD, Xu Y, Yin L, Ge X, Jadhav K, Adorini L, Zhang Y. Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis. Hepatology 2014;59:1761-71.
79. Xu J, Xu Y, Li Y, Jadhav K, You M, Yin L, Zhang Y. Carboxylesterase 1 is regulated by hepatocyte nuclear factor 4alpha and protects against alcohol- and MCD dietinduced Liver Injury. Sci Rep. 2016;6:24277.
80. Liu H, Beier JI, Arteel GE, Ramsden CE, Feldstein AE, McClain CJ, Kirpich IA. Transient receptor potential vanilloid 1 gene deficiency ameliorates hepatic injury in a mouse model of chronic binge alcohol-induced alcoholic liver disease. Am J Pathol. 2015;185:43-54.
81. Wang L, Liangpunsakul S. Circadian clock control of hepatic lipid metabolism: Role of small heterodimer partner (Shp). J Investig Med. 2016;64:1158-61.
82. Yang Z, Tsuchiya H, Zhang Y, Lee S, Liu C, Huang Y, Vargas GM, Wang L. REV-ERBalpha activates C/EBP homologous protein to control small heterodimer partnermediated oscillation of alcoholic fatty liver. Am J Pathol. 2016;186:2909-2920.
83. Tsuchiya H, da Costa KA, Lee S, Renga B, Jaeschke H, Yang Z, Orena SJ, Goedken MJ, Zhang Y, Kong B, Lebofsky M, Rudraiah S, Smalling R, Guo G, Fiorucci S, Zeisel SH, Wang L. Interactions between nuclear receptor SHP and FOXA1 maintain oscillatory homocysteine homeostasis in mice. Gastroenterology 2015;148:1012- 23.e14.
84. Tran M, Yang Z, Liangpunsakul S, Wang L. Metabolomics analysis revealed distinct cyclic changes of metabolites altered by chronic ethanol-plus-binge and shp deficiency. Alcohol Clin Exp Res. 2016;40:2548-56.
85. Park JE, Lee M, Mifflin R, Lee YK. Enhanced ethanol catabolism in orphan nuclear receptor SHP-null mice. Am J Physiol Gastrointest Liver Physiol. 2016;310:G799-807.
86. Gu J, Zhang Y, Xu D, Zhao Z, Zhang Y, Pan Y, Cao P, Wang Z, Chen Y. Ethanol-induced hepatic steatosis is modulated by glycogen level in the liver. J Lipid Res. 2015;56:1329-39.
87. Kang DJ, Betrapally NS, Ghosh SA, Sartor RB, Hylemon PB, Gillevet PM, Sanyal AJ, Heuman DM, Carl D, Zhou H, Liu R, Wang X, Yang J, Jiao C, Herzog J, Lippman HR, Sikaroodi M, Brown RR, Bajaj JS. Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice. Hepatology 2016;64:1232-48.
88. Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology 2015;148:30-6.
89. Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut 2016;65:2035-44.
90. Inamine T, Yang AM, Wang L, Lee KC, Llorente C, Schnabl B. Genetic loss of immunoglobulin A does not influence development of alcoholic steatohepatitis in mice. Alcohol Clin Exp Res. 2016;40:2604-13.
91. Ganesan M, Hindman J, Tillman B, Jaramillo L, Poluektova LI, French BA, Kharbanda KK, French SW, Osna NA. FAT10 suppression stabilizes oxidized proteins in liver cells: Effects of HCV and ethanol. Exp Mol Pathol. 2015;99:506-16.
92. Kong X, Feng D, Mathews S, Gao B. Hepatoprotective and anti-fibrotic functions of interleukin-22: Therapeutic potential for the treatment of alcoholic liver disease. J Gastroenterol Hepatol. 2013;28(Suppl 1):56-60.
93. Gao B, Shah VH. Combination therapy: New hope for alcoholic hepatitis? Clin Res Hepatol Gastroenterol. 2015;39(Suppl 1):S7-S11.
94. Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, Barrieau M, Min SY, Kurt-Jones EA, Szabo G. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122: 3476-89.
95. Tilg H, Moschen AR, Szabo G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2016;64:955-65.
96. Ambade A, Catalano D, Lim A, Kopoyan A, Shaffer SA, Mandrekar P. Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury. J Hepatol. 2014;61:903-11.
97. Bai T, Yang Y, Yao YL, Sun P, Lian LH, Wu YL, Nan JX. Betulin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK signaling pathway. Pharmacol Res. 2016;105:1-12.
98. Liu G, Zhang Y, Liu C, Xu D, Zhang R, Cheng Y, Pan Y, Huang C, Chen Y. Luteolin alleviates alcoholic liver disease induced by chronic and binge ethanol feeding in mice. J Nutr. 2014;144:1009-15.
99. Chen RC, Xu LM, Du SJ, Huang SS, Wu H, Dong JJ, Huang JR, Wang XD, Feng WK, Chen YP. Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding. Toxicol Lett. 2016;241:103-10.
100. Han JY, Lee S, Yang JH, Kim S, Sim J, Kim MG, Jeong TC, Ku SK, Cho IJ, Ki SH. Korean Red Ginseng attenuates ethanol-induced steatosis and oxidative stress via AMPK/Sirt1 activation. J Ginseng Res. 2015;39:105-15.
101. Song X, Yin S, Huo Y, Liang M, Fan L, Ye M, Hu H. Glycycoumarin ameliorates alcohol-induced hepatotoxicity via activation of Nrf2 and autophagy. Free Radic Biol Med. 2015;89:135-46.
102. Wang M, Zhang XJ, Feng K, He C, Li P, Hu YJ, Su H, Wan JB. Dietary alpha-linolenic acid-rich flaxseed oil prevents against alcoholic hepatic steatosis via ameliorating lipid homeostasis at adipose tissue-liver axis in mice. Sci Rep. 2016;6:26826.
103. Yang Y, Bai T, Yao YL, Zhang DQ, Wu YL, Lian LH, Nan JX. Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicol Lett. 2016;262:80-91.
104. Varga ZV, Matyas C, Erdelyi K, Cinar R, Nieri D, Chicca A, Nemeth BT, Paloczi J, Lajtos T, Corey L, Hasko G, Gao B, Kunos G, Gertsch J, Pacher P. Beta-caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. Br J Pharmacol. 2017 (Epub ahead of print).