Characterizing the Mechanism Behind the Progression of NAFLD to Hepatocellular Carcinoma

References

• YounossiZ, AnsteeQM, MariettiMet al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15(1), 11–20 (2018).
   PubMed Web of Science ®Google Scholar
• EstesC, RazaviH, LoombaR, YounossiZ, SanyalAJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67(1), 123–133 (2018).
   PubMed Web of Science ®Google Scholar
• BaffyG, BruntEM, CaldwellSH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J. Hepatol. 56(6), 1384–1391 (2012).
   PubMed Web of Science ®Google Scholar
• KleinS, DufourJF. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Hepat. Oncol. 4(3), 83–98 (2017).
   PubMedGoogle Scholar
• WhiteDL, KanwalF, El-SeragHB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin. Gastroenterol. Hepatol. 10(12), 1342–1359, e1342 (2012).
   PubMed Web of Science ®Google Scholar
• KanwalF, KramerJR, MapakshiSet al.Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 155(6), 1828–1837, e1822 (2018).
   PubMed Web of Science ®Google Scholar
• SanyalA, PoklepovicA, MoyneurE, BarghoutV. Population-based risk factors and resource utilization for HCC: US perspective. Curr. Med. Res. Opin. 26(9), 2183–2191 (2010).
   PubMed Web of Science ®Google Scholar
• European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J. Hepatol. 69(1), 182–236 (2018).
   PubMed Web of Science ®Google Scholar
• HeimbachJK, KulikLM, FinnRSet al.AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67(1), 358–380 (2018).
   PubMed Web of Science ®Google Scholar
• KawamuraY, AraseY, IkedaKet al.Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am. J. Gastroenterol. 107(2), 253–261 (2012).
   PubMed Web of Science ®Google Scholar
• LoombaR, LimJK, PattonH, El-SeragHB. AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review. Gastroenterology 158(6), 1822–1830 (2020).
   PubMed Web of Science ®Google Scholar
• SingalAG, LamperticoP, NahonP. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J. Hepatol. 72(2), 250–261 (2020).
   PubMed Web of Science ®Google Scholar
• KimHL, AnJ, ParkJA, ParkSH, LimYS, LeeEK. Magnetic resonance imaging is cost-effective for hepatocellular carcinoma surveillance in high risk patients with cirrhosis. Hepatology 69(4),1599–1613 (2019).
   PubMed Web of Science ®Google Scholar
• KimSY, AnJ, LimYSet al.MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma. JAMA Oncol. 3(4), 456–463 (2017).
   PubMed Web of Science ®Google Scholar
• EslamM, ValentiL, RomeoS. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68(2), 268–279 (2018).
   PubMed Web of Science ®Google Scholar
• SchwimmerJB, CeledonMA, LavineJEet al.Heritability of nonalcoholic fatty liver disease. Gastroenterology 136(5), 1585–1592 (2009).
   PubMed Web of Science ®Google Scholar
• AnsteeQM, ReevesHL, KotsilitiE, GovaereO, HeikenwalderM. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16(7), 411–428 (2019).
   PubMed Web of Science ®Google Scholar
• RomeoS, KozlitinaJ, XingCet al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40(12), 1461–1465 (2008).
   PubMed Web of Science ®Google Scholar
• KozlitinaJ, SmagrisE, StenderSet al.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46(4), 352–356 (2014).
   PubMed Web of Science ®Google Scholar
• MancinaRM, DongiovanniP, PettaSet al.The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150(5), 1219–1230, e1216 (2016).
   PubMed Web of Science ®Google Scholar
• Abul-HusnNS, ChengX, LiAHet al.A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378(12), 1096–1106 (2018).
   PubMed Web of Science ®Google Scholar
• DongiovanniP, RomeoS, ValentiL. Genetic factors in the pathogenesis of nonalcoholic fatty liver and steatohepatitis. Biomed. Res. Int. 2015, 460190 (2015).
   PubMed Web of Science ®Google Scholar
• Vespasiani-GentilucciU, GalloP, Dell’untoC, VolpentestaM, Antonelli-IncalziR, PicardiA. Promoting genetics in non-alcoholic fatty liver disease: combined risk score through polymorphisms and clinical variables. World J. Gastroenterol. 24(43), 4835–4845 (2018).
   PubMed Web of Science ®Google Scholar
• TrepoE, NahonP, BontempiGet al.Association between the PNPLA3 (rs738409 C > G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology 59(6), 2170–2177 (2014).
   PubMed Web of Science ®Google Scholar
• HuangY, CohenJC, HobbsHH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J. Biol. Chem. 286(43), 37085–37093 (2011).
   PubMed Web of Science ®Google Scholar
• PirazziC, AdielsM, BurzaMAet al.Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57(6), 1276–1282 (2012).
   PubMed Web of Science ®Google Scholar
• YuanX, WaterworthD, PerryJRet al.Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83(4), 520–528 (2008).
   PubMed Web of Science ®Google Scholar
• KolleritsB, CoassinS, KiechlSet al.A common variant in the adiponutrin gene influences liver enzyme values. J. Med. Genet. 47(2), 116–119 (2010).
   PubMed Web of Science ®Google Scholar
• ChambersJC, ZhangW, SehmiJet al.Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43(11), 1131–1138 (2011).
   PubMed Web of Science ®Google Scholar
• ValentiL, Al-SerriA, DalyAKet al.Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51(4), 1209–1217 (2010).
   PubMed Web of Science ®Google Scholar
• SpeliotesEK, ButlerJL, PalmerCD, VoightBF, HirschhornJN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 52(3), 904–912 (2010).
   PubMed Web of Science ®Google Scholar
• RotmanY, KohC, ZmudaJM, KleinerDE, LiangTJ. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52(3), 894–903 (2010).
   PubMed Web of Science ®Google Scholar
• HolmenOL, ZhangH, FanYet al.Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat. Genet. 46(4), 345–351 (2014).
   PubMed Web of Science ®Google Scholar
• MaY, BelyaevaOV, BrownPMet al.17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease. Hepatology 69(4), 1504–1519 (2019).
   PubMed Web of Science ®Google Scholar
• MancinaRM, DongiovanniP, PettaSet al.The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150(5), 1219.e6–1230.e6 (2016).
   Web of Science ®Google Scholar
• LiuYL, PatmanGL, LeathartJBet al.Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 61(1), 75–81 (2014).
   PubMed Web of Science ®Google Scholar
• DonatiB, DongiovanniP, RomeoSet al.MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci. Rep. 7(1), 4492 (2017).
   PubMedGoogle Scholar
• FalletiE, CussighA, CmetS, FabrisC, ToniuttoP. PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis. Dig. Liver Dis. 48(1), 69–75 (2016).
   PubMedGoogle Scholar
• YangJ, TrepoE, NahonPet al.A 17-beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease. Hepatology 70(1), 231–240 (2019).
   PubMed Web of Science ®Google Scholar
• LiL, CheL, TharpKMet al.Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans. Hepatology 63(6), 1900–1913 (2016).
   PubMed Web of Science ®Google Scholar
• NaultJC, NahonP. Genetic predisposition to hepatocellular carcinoma in alcoholic cirrhosis: the NCAN-PNPLA3-lipid connection?J. Hepatol. 61(5), 971–972 (2014).
   PubMed Web of Science ®Google Scholar
• NahonP, Zucman-RossiJ. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J. Hepatol. 57(3), 663–674 (2012).
   PubMed Web of Science ®Google Scholar
• NahonP, NaultJC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int. 37(11), 1591–1601 (2017).
   PubMed Web of Science ®Google Scholar
• NahonP, SuttonA, ZiolM, Zucman-RossiJ, TrinchetJC, Ganne-CarrieN. Genetic risk markers for hepatocellular carcinoma in patients with alcoholic liver disease. Hepat. Oncol. 2(1), 63–78 (2015).
   PubMedGoogle Scholar
• Ganne-CarrieN, NahonP. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J. Hepatol. 70(2), 284–293 (2019).
   PubMed Web of Science ®Google Scholar
• GuyotE, SuttonA, RufatPet al.PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis. J. Hepatol. 58(2), 312–318 (2013).
   PubMed Web of Science ®Google Scholar
• YangJ, TrepoE, NahonPet al.PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Int. J. Cancer 144(3), 533–544 (2019).
   PubMed Web of Science ®Google Scholar
• BurzaMA, PirazziC, MaglioCet al.PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig. Liver Dis. 44(12), 1037–1041 (2012).
   PubMedGoogle Scholar
• GrimaudoS, PipitoneRM, PennisiGet al.Association between PNPLA3 rs738409 C > G variant and liver-related outcomes in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 18(4), 935–944e933 (2020).
   PubMed Web of Science ®Google Scholar
• Gellert-KristensenH, RichardsonTG, DaveySmith G, NordestgaardBG, Tybjaerg-HansenA, StenderS. Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population. Hepatology 72(3), 845–856 (2020).
   PubMed Web of Science ®Google Scholar
• SugrueLP, DesikanRS. What are polygenic scores and why are they important?JAMA 321(18), 1820–1821 (2019).
   PubMed Web of Science ®Google Scholar
• MarraF, LotersztajnS. Pathophysiology of NASH: perspectives for a targeted treatment. Curr. Pharm. Des. 19(29), 5250–5269 (2013).
   PubMed Web of Science ®Google Scholar
• MotaM, BaniniBA, CazanaveSC, SanyalAJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 65(8), 1049–1061 (2016).
   PubMed Web of Science ®Google Scholar
• BoursierJ, MuellerO, BarretMet al.The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63(3), 764–775 (2016).
   PubMed Web of Science ®Google Scholar
• MeekTH, MortonGJ. The role of leptin in diabetes: metabolic effects. Diabetologia 59(5), 928–932 (2016).
   PubMed Web of Science ®Google Scholar
• MallatA, LotersztajnS. Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis. Am. J. Physiol. Cell Physiol. 305(8), C789–799 (2013).
   PubMed Web of Science ®Google Scholar
• Svegliati-BaroniG, RidolfiF, DiSario Aet al.Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology 29(6), 1743–1751 (1999).
   PubMed Web of Science ®Google Scholar
• PradereJP, TroegerJS, DapitoDH, MencinAA, SchwabeRF. Toll-like receptor 4 and hepatic fibrogenesis. Semin. Liver Dis. 30(3), 232–244 (2010).
   PubMed Web of Science ®Google Scholar
• MarraF, Svegliati-BaroniG. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 68(2), 280–295 (2018).
   PubMed Web of Science ®Google Scholar
• KunneC, AccoA, DuijstSet al.FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model. Biochim. Biophys. Acta 1842(5), 739–746 (2014).
   PubMed Web of Science ®Google Scholar
• McbrideRL, FeringaER, SmithBE. The fate of prelabeled Clarke’s column neurons after axotomy. Exp. Neurol. 102(2), 236–243 (1988).
   PubMed Web of Science ®Google Scholar
• KettnerNM, VoicuH, FinegoldMJet al.Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell 30(6), 909–924 (2016).
   PubMed Web of Science ®Google Scholar
• TovarV, AlsinetC, VillanuevaAet al.IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J. Hepatol. 52(4), 550–559 (2010).
   PubMed Web of Science ®Google Scholar
• ChettouhH, LequoyM, FartouxL, VigourouxC, Desbois-MouthonC. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 35(10), 2203–2217 (2015).
   PubMed Web of Science ®Google Scholar
• MichelottiGA, MachadoMV, DiehlAM. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10(11), 656–665 (2013).
   PubMed Web of Science ®Google Scholar
• AllaireM, NaultJC. Type 2 diabetes-associated hepatocellular carcinoma: a molecular profile. Clin. Liver Dis. (Hoboken) 8(2), 53–58 (2016).
   PubMedGoogle Scholar
• HaczeyniF, YehMM, IoannouGNet al.Mouse models of non-alcoholic steatohepatitis: a reflection on recent literature. J. Gastroenterol. Hepatol. 33(7), 1312–1320 (2018).
   PubMed Web of Science ®Google Scholar
• MachadoMV, MichelottiGA, XieGet al.Correction: mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS ONE 10(6), e0132315 (2015).
   PubMed Web of Science ®Google Scholar
• IbrahimSH, HirsovaP, MalhiH, GoresGJ. Animal models of nonalcoholic steatohepatitis: eat, delete, and inflame. Dig. Dis. Sci. 61(5), 1325–1336 (2016).
   PubMed Web of Science ®Google Scholar
• MiuraK, KodamaY, InokuchiSet al.Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139(1), 323–334, e327 (2010).
   PubMed Web of Science ®Google Scholar
• DowmanJK, HopkinsLJ, ReynoldsGMet 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. 184(5), 1550–1561 (2014).
   PubMed Web of Science ®Google Scholar
• WolfMJ, AdiliA, PiotrowitzKet al.Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26(4), 549–564 (2014).
   PubMed Web of Science ®Google Scholar
• FarrellGC, MridhaAR, YehMMet al.Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver Int. 34(7), 1084–1093 (2014).
   PubMed Web of Science ®Google Scholar
• HaluzikM, ColomboC, GavrilovaOet al.Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology 145(7), 3258–3264 (2004).
   PubMed Web of Science ®Google Scholar
• GanzM, CsakT, SzaboG. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation. World J. Gastroenterol. 20(26), 8525–8534 (2014).
   PubMed Web of Science ®Google Scholar
• FujiiM, ShibazakiY, WakamatsuKet al.A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med. Mol. Morphol. 46(3), 141–152 (2013).
   PubMed Web of Science ®Google Scholar
• RidolfiR, AmaducciL, DerniS, FabbriL, InnocentiMP, VignutelliP. Chemotherapy with 5-fluorouracil and streptozotocin in carcinoid tumors of gastrointestinal origin: experiences with 13 patients. J. Chemother. 3(5), 328–331 (1991).
   PubMed Web of Science ®Google Scholar
• KishidaN, MatsudaS, ItanoOet al.Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine. BMC Gastroenterol. 16(1), 61 (2016).
   PubMedGoogle Scholar
• TsuchidaT, LeeYA, FujiwaraNet al.Corrigendum to ‘A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer’. [ J. Hepatol.69, 385–395 (2018)]. J. Hepatol. 69(4), 988 (2018).
   PubMed Web of Science ®Google Scholar
• LindstromP. The physiology of obese-hyperglycemic mice [ob/ob mice]. Sci. World J. 7, 666–685 (2007).
   Web of Science ®Google Scholar
• WangB, ChandrasekeraPC, PippinJJ. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr. Diabetes Rev. 10(2), 131–145 (2014).
   PubMedGoogle Scholar
• ZhangN, ChuES, ZhangJet al.Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-kappaB signaling pathway. Oncotarget 5(18), 8330–8340 (2014).
   PubMedGoogle Scholar
• ItohM, SuganamiT, NakagawaNet al.Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am. J. Pathol. 179(5), 2454–2463 (2011).
   PubMed Web of Science ®Google Scholar
• HorieY, SuzukiA, KataokaEet al.Hepatocyte-specific PTEN deficiency results in steatohepatitis and hepatocellular carcinomas. J. Clin. Invest. 113(12), 1774–1783 (2004).
   PubMed Web of Science ®Google Scholar
• FanCY, PanJ, ChuRet al.Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene. J. Biol. Chem. 271(40), 24698–24710 (1996).
   PubMed Web of Science ®Google Scholar
• LuSC, MatoJM. Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer. Alcohol 35(3), 227–234 (2005).
   PubMed Web of Science ®Google Scholar
• BonzoJA, FerryCH, MatsubaraT, KimJH, GonzalezFJ. Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4alpha in adult mice. J. Biol. Chem. 287(10), 7345–7356 (2012).
   PubMed Web of Science ®Google Scholar
• FekryB, Ribas-LatreA, BaumgartnerCet al.HNF4alpha-deficient fatty liver provides a permissive environment for sex-independent hepatocellular carcinoma. Cancer Res. 79(22), 5860–5873 (2019).
   PubMed Web of Science ®Google Scholar
• Van RooyenDM, LarterCZ, HaighWGet al.Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology 141(4), 1393–1403; e1391–e1395 (2011).
   PubMed Web of Science ®Google Scholar
• ArfiantiE, LarterCZ, LeeSet al.Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-kappaB or Akt/mTORC1. J. Clin. Transl. Res. 2(1), 26–37 (2016).
   PubMedGoogle Scholar
• AsgharpourA, CazanaveSC, PacanaTet al.A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J. Hepatol. 65(3), 579–588 (2016).
   PubMed Web of Science ®Google Scholar
• NakagawaH, UmemuraA, TaniguchiKet al.ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26(3), 331–343 (2014).
   PubMed Web of Science ®Google Scholar
• KimG, JangSY, NamCM, KangES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J. Hepatol. 68(3), 476–484 (2018).
   PubMed Web of Science ®Google Scholar
• ParadisV, ZalinskiS, ChelbiEet al.Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49(3), 851–859 (2009).
   PubMed Web of Science ®Google Scholar
• HirosumiJ, TuncmanG, ChangLet al.A central role for JNK in obesity and insulin resistance. Nature 420(6913), 333–336 (2002).
   PubMed Web of Science ®Google Scholar
• GomesAL, TeijeiroA, BurenSet al.Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30(1), 161–175 (2016).
   PubMed Web of Science ®Google Scholar
• GentricG, MailletV, ParadisVet al.Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J. Clin. Invest. 125(3), 981–992 (2015).
   PubMed Web of Science ®Google Scholar
• VillanuevaA, ChiangDY, NewellPet al.Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135(6), 1972–1983, e1971–e1911 (2008).
   PubMed Web of Science ®Google Scholar
• HotamisligilGS, PeraldiP, BudavariA, EllisR, WhiteMF, SpiegelmanBM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271(5249), 665–668 (1996).
   PubMed Web of Science ®Google Scholar
• KohJH, ShinYG, NamSM, LeeMY, ChungCH, ShinJY. Serum adipocyte fatty acid-binding protein levels are associated with nonalcoholic fatty liver disease in type 2 diabetic patients. Diabetes Care 32(1), 147–152 (2009).
   PubMed Web of Science ®Google Scholar
• LaouiremS, SannierA, NorkowskiEet al.Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome. Oncogene 38(16), 3033–3046 (2019).
   PubMed Web of Science ®Google Scholar
• JansenPL. Endogenous bile acids as carcinogens. J. Hepatol. 47(3), 434–435 (2007).
   PubMedGoogle Scholar
• DapitoDH, MencinA, GwakGYet al.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21(4), 504–516 (2012).
   PubMed Web of Science ®Google Scholar
• YoshimotoS, LooTM, AtarashiKet al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499(7456), 97–101 (2013).
   PubMed Web of Science ®Google Scholar
• AllaireM, RautouPE, CodognoP, LotersztajnS. Autophagy in liver diseases: time for translation?J. Hepatol. 70(5), 985–998 (2019).
   PubMed Web of Science ®Google Scholar
• HammouteneA, BiquardL, LasselinJet al.A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J. Hepatol. 72(3), 528–538 (2020).
   PubMed Web of Science ®Google Scholar
• RybsteinMD, Bravo-SanPedro JM, KroemerG, GalluzziL. The autophagic network and cancer. Nat. Cell Biol. 20(3), 243–251 (2018).
   PubMed Web of Science ®Google Scholar
• TakamuraA, KomatsuM, HaraTet al.Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25(8), 795–800 (2011).
   PubMed Web of Science ®Google Scholar
• DhanasekaranR, NaultJC, RobertsLR, Zucman-RossiJ. Genomic medicine and implications for hepatocellular carcinoma prevention and therapy. Gastroenterology 156(2), 492–509 (2019).
   PubMed Web of Science ®Google Scholar
• SchulzeK, ImbeaudS, LetouzeEet al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47(5), 505–511 (2015).
   PubMed Web of Science ®Google Scholar
• TotokiY, TatsunoK, CovingtonKRet al.Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46(12), 1267–1273 (2014).
   PubMed Web of Science ®Google Scholar
• NaultJC, MartinY, CarusoSet al.Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma. Hepatology 71(1), 164–182 (2020).
   PubMed Web of Science ®Google Scholar
• SungWK, ZhengH, LiSet al.Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 44(7), 765–769 (2012).
   PubMed Web of Science ®Google Scholar
• LetouzeE, ShindeJ, RenaultVet al.Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat Commun 8(1), 1315 (2017).
   PubMedGoogle Scholar
• NaultJC, LetouzeE. Mutational processes in hepatocellular carcinoma: the story of aristolochic acid. Semin. Liver Dis. 39(3), 334–340 (2019).
   PubMed Web of Science ®Google Scholar
• BressacB, KewM, WandsJ, OzturkM. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350(6317), 429–431 (1991).
   PubMed Web of Science ®Google Scholar
• NaultJC, CouchyG, BalabaudCet al.Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology 152(4), 880–894, e886 (2017).
   PubMed Web of Science ®Google Scholar
• BayardQ, CarusoS, CouchyGet al.Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas. Gut 69(9), 1667–1676 (2020).
   PubMed Web of Science ®Google Scholar
• Cancer Genome Atlas Research Network. Electronic Address WBE, Cancer Genome Atlas Research N. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169(7), 1327–1341, e1323 (2017).
   PubMed Web of Science ®Google Scholar
• FargesO, FerreiraN, DokmakS, BelghitiJ, BedossaP, ParadisV. Changing trends in malignant transformation of hepatocellular adenoma. Gut 60(1), 85–89 (2011).
   PubMed Web of Science ®Google Scholar
• PilatiC, LetouzeE, NaultJCet al.Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 25(4), 428–441 (2014).
   PubMed Web of Science ®Google Scholar
• ParadisV, ChampaultA, RonotMet al.Telangiectatic adenoma: an entity associated with increased body mass index and inflammation. Hepatology 46(1), 140–146 (2007).
   PubMed Web of Science ®Google Scholar
• ParadisV, AlbuquerqueM, MebarkiMet al.Cullin7: a new gene involved in liver carcinogenesis related to metabolic syndrome. Gut 62(6), 911–919 (2013).
   PubMed Web of Science ®Google Scholar
• SalomaoM, YuWM, BrownRSJr, EmondJC, LefkowitchJH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am. J. Surg. Pathol. 34(11), 1630–1636 (2010).
   PubMed Web of Science ®Google Scholar
• SalomaoM, RemottiH, VaughanR, SiegelAB, LefkowitchJH, MoreiraRK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum. Pathol. 43(5), 737–746 (2012).
   PubMedGoogle Scholar
• JainD, NayakNC, KumaranV, SaigalS. Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. Arch. Pathol. Lab. Med. 137(7), 961–966 (2013).
   PubMed Web of Science ®Google Scholar
• ShibaharaJ, AndoS, SakamotoY, KokudoN, FukayamaM. Hepatocellular carcinoma with steatohepatitic features: a clinicopathological study of Japanese patients. Histopathology 64(7), 951–962 (2014).
   PubMed Web of Science ®Google Scholar
• AndoS, ShibaharaJ, HayashiA, FukayamaM. beta-catenin alteration is rare in hepatocellular carcinoma with steatohepatitic features: immunohistochemical and mutational study. Virchows Arch. 467(5), 535–542 (2015).
   PubMed Web of Science ®Google Scholar
• LeeJ, LeeS, ZhangH, HillMA, ZhangC, ParkY. Interaction of IL-6 and TNF-alpha contributes to endothelial dysfunction in type 2 diabetic mouse hearts. PLoS ONE 12(11), e0187189 (2017).
   PubMed Web of Science ®Google Scholar
• Zucman-RossiJ, VillanuevaA, NaultJC, LlovetJM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149(5), 1226–1239, e1224 (2015).
   PubMed Web of Science ®Google Scholar
• BoyaultS, RickmanDS, DeReynies Aet al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45(1), 42–52 (2007).
   PubMed Web of Science ®Google Scholar
• CalderaroJ, CouchyG, ImbeaudSet al.Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J. Hepatol. 67(4), 727–738 (2017).
   PubMed Web of Science ®Google Scholar
• YehMM, LiuY, TorbensonM. Steatohepatitic variant of hepatocellular carcinoma in the absence of metabolic syndrome or background steatosis: a clinical, pathological, and genetic study. Hum. Pathol. 46(11), 1769–1775 (2015).
   PubMed Web of Science ®Google Scholar