REFERENCES
1. Younossi ZM, Corey KE, Lim JK. AGA clinical practice update on lifestyle modification using diet and exercise to achieve weight loss in the management of nonalcoholic fatty liver disease: expert review. Gastroenterology 2021;160:912-8.
2. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020;73:202-9.
3. Younossi ZM, Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep 2021;3:100305.
4. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18:223-38.
5. Loomba R, Lim JK, Patton H, El-Serag HB. AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review. Gastroenterology 2020;158:1822-30.
6. Nahon P, Allaire M, Nault JC, Paradis V. Characterizing the mechanism behind the progression of NAFLD to hepatocellular carcinoma. Hepat Oncol 2020;7:HEP36.
7. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol 2018;68:268-79.
8. Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem 2011;286:37085-93.
9. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-5.
10. BasuRay S, Wang Y, Smagris E, Cohen JC, Hobbs HH. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci U S A 2019;116:9521-6.
11. He S, McPhaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010;285:6706-15.
12. Pirazzi C, Adiels M, Burza MA, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 2012;57:1276-82.
13. Yuan X, Waterworth D, Perry JR, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 2008;83:520-8.
14. Speliotes EK, Butler JL, Palmer CD, Voight BF, Hirschhorn JN. GIANT Consortium, MIGen Consortium, NASH CRN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010;52:904-12.
15. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ. NASH CRN. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010;52:894-903.
16. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883-94.
17. Salameh H, Hanayneh MA, Masadeh M, et al. PNPLA3 as a genetic determinant of risk for and severity of non-alcoholic fatty liver disease spectrum. J Clin Transl Hepatol 2016;4:175-91.
18. Falleti E, Fabris C, Cmet S, et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int 2011;31:1137-43.
19. Trépo E, Nahon P, Bontempi G, et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology 2014;59:2170-7.
20. Burza MA, Pirazzi C, Maglio C, et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis 2012;44:1037-41.
21. Liu YL, Patman GL, Leathart JB, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014;61:75-81.
22. Seko Y, Sumida Y, Tanaka S, et al. Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression. Hepatol Res 2017;47:1083-92.
23. Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014;46:352-6.
24. Prill S, Caddeo A, Baselli G, et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci Rep 2019;9:11585.
25. Dongiovanni P, Petta S, Maglio C, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015;61:506-14.
26. Newberry EP, Hall Z, Xie Y, et al. Liver-specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis, and hepatocellular cancer. Hepatology 2021;74:1203-19.
27. Yang J, Trépo E, Nahon P, et al. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Int J Cancer 2019;144:533-44.
28. Liu YL, Reeves HL, Burt AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014;5:4309.
29. Tanaka Y, Shimanaka Y, Caddeo A, et al. LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut 2021;70:180-93.
30. Meroni M, Longo M, Fracanzani AL, Dongiovanni P. MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD. EBioMedicine 2020;57:102866.
31. Buch S, Stickel F, Trépo E, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet 2015;47:1443-8.
32. Freund C, Wahlers A, Begli NH, et al. The MBOAT7 rs641738 variant is associated with an improved outcome in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2020;44:646-52.
33. Thabet K, Chan HLY, Petta S, et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology 2017;65:1840-50.
34. Donati B, Dongiovanni P, Romeo S, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep 2017;7:4492.
35. Teo K, Abeysekera KWM, Adams L, et al. EU-PNAFLD Investigators, GOLD Consortium. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: a meta-analysis. J Hepatol 2021;74:20-30.
36. Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med 2018;378:1096-106.
37. Pirola CJ, Garaycoechea M, Flichman D, et al. Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease. J Lipid Res 2019;60:176-85.
38. Stickel F, Lutz P, Buch S, et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology 2020;72:88-102.
39. Kozlitina J, Stender S, Hobbs HH, Cohen JC. HSD17B13 and chronic liver disease in blacks and hispanics. N Engl J Med 2018;379:1876-7.
40. Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012;55:781-9.
41. Petta S, Miele L, Bugianesi E, et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS One 2014;9:e87523.
42. Meroni M, Longo M, Paolini E, et al. The rs599839 A>G variant disentangles cardiovascular risk and hepatocellular carcinoma in NAFLD patients. Cancers (Basel) 2021;13:1783.
43. Pelusi S, Baselli G, Pietrelli A, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep 2019;9:3682.
44. Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int 2016;36:317-24.
45. Kanwal F, Kramer JR, Li L, et al. Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease. Hepatology 2020;71:808-19.
46. Simon TG, King LY, Chong DQ, et al. Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies. Hepatology 2018;67:1797-806.
47. Kucukoglu O, Sowa JP, Mazzolini GD, Syn WK, Canbay A. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol 2021;74:442-57.
48. Grohmann M, Wiede F, Dodd GT, et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 2018;175:1289-1306.e20.
50. Allaire M, Nault JC. Type 2 diabetes-associated hepatocellular carcinoma: a molecular profile. Clin Liver Dis (Hoboken) 2016;8:53-8.
51. Sutti S, Albano E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat Rev Gastroenterol Hepatol 2020;17:81-92.
52. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450-6.
53. van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 2018;68:1347-60.
54. Shalapour S, Lin X, Bastian IN, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017;551:340-5.
55. Malehmir M, Pfister D, Gallage S, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 2019;25:641-55.
56. Simon TG, Ma Y, Ludvigsson JF, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol 2018;4:1683-90.
57. Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med 2020;382:1018-28.
58. Krenkel O, Hundertmark J, Abdallah AT, et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 2020;69:551-63.
59. Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology 2019;69:107-20.
60. Zhou J, Tripathi M, Sinha RA, Singh BK, Yen PM. Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease. Hepatoma Res 2021;7:11.
61. Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun 2021;12:187.
62. Conde de la Rosa L, Garcia-Ruiz C, Vallejo C, et al. STARD1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway. J Hepatol 2021;74:1429-41.
63. Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol 2018;68:280-95.
64. Pinyol R, Torrecilla S, Wang H, et al. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2021;75:865-78.
65. Paradis V, Albuquerque M, Mebarki M, et al. Cullin7: a new gene involved in liver carcinogenesis related to metabolic syndrome. Gut 2013;62:911-9.
66. Wang B, Li X, Hu W, Zhou Y, Din Y. Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization. IUBMB Life 2019;71:1952-61.
67. Tian Y, Arai E, Makiuchi S, et al. Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas. J Cancer Res Clin Oncol 2020;146:2461-77.
68. Rietman A, Sluik D, Feskens EJM, Kok FJ, Mensink M. Associations between dietary factors and markers of NAFLD in a general Dutch adult population. Eur J Clin Nutr 2018;72:117-23.
69. Kohli R, Kirby M, Xanthakos SA, et al. High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis. Hepatology 2010;52:934-44.
70. Charlton M, Krishnan A, Viker K, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 2011;301:G825-34.
71. Dowman JK, Hopkins LJ, Reynolds GM, et al. Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle. Am J Pathol 2014;184:1550-61.
72. Harris SE, Poolman TM, Arvaniti A, Cox RD, Gathercole LL, Tomlinson JW. The American lifestyle-induced obesity syndrome diet in male and female rodents recapitulates the clinical and transcriptomic features of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2020;319:G345-60.
73. Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 2014;26:549-64.
74. Wei G, An P, Vaid KA, et al. Comparison of murine steatohepatitis models identifies a dietary intervention with robust fibrosis, ductular reaction, and rapid progression to cirrhosis and cancer. Am J Physiol Gastrointest Liver Physiol 2020;318:G174-88.
75. Fujii M, Shibazaki Y, Wakamatsu K, et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol 2013;46:141-52.
76. Santhekadur PK, Kumar DP, Sanyal AJ. Preclinical models of non-alcoholic fatty liver disease. J Hepatol 2018;68:230-7.
77. Tsuchida T, Lee YA, Fujiwara N, et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol 2018;69:385-95.
78. Asgharpour A, Cazanave SC, Pacana T, et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol 2016;65:579-88.
79. Nakagawa H, Umemura A, Taniguchi K, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 2014;26:331-43.
80. Umemura A, He F, Taniguchi K, et al. p62, Upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 2016;29:935-48.
81. Bissig-Choisat B, Alves-Bezerra M, Zorman B, et al. A human liver chimeric mouse model for non-alcoholic fatty liver disease. JHEP Rep 2021;3:100281.
82. Yoshioka N, Tanaka M, Ochi K, et al. The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model. Biomed Pharmacother 2021;140:111738.
83. Association for the Study of the Liver. Electronic address: [email protected], European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182-236.
84. Younes R, Caviglia GP, Govaere O, et al. Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease. J Hepatol 2021;75:786-94.
85. Best J, Bechmann LP, Sowa JP, et al. GALAD score detects early hepatocellular carcinoma in an international cohort of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2020;18:728-35.e4.
86. Dongiovanni P, Stender S, Pietrelli A, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med 2018;283:356-70.
87. Gellert-Kristensen H, Richardson TG, Davey Smith G, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population. Hepatology 2020;72:845-56.
