Molecular Genealogy of Metabolic-associated Hepatocellular Carcinoma

 

 Permissions and Reprints

Abstract

This review examines the latest epidemiological and molecular pathogenic findings of metabolic-associated hepatocellular carcinoma (HCC). Its increasing prevalence is a significant concern and reflects the growing burden of obesity and metabolic diseases, including metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, and type 2 diabetes. Metabolic-associated HCC has unique molecular abnormality and distinctive gene expression patterns implicating aberrations in bile acid, fatty acid metabolism, oxidative stress, and proinflammatory pathways. Furthermore, a notable frequency of single nucleotide polymorphisms in genes such as patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, and membrane-bound O-acyltransferase domain-containing 7 has been observed. The tumor immune microenvironment of metabolic-associated HCC is characterized by unique phenotypes of macrophages, neutrophils, and T lymphocytes. Additionally, the pathogenesis of metabolic-associated HCC is influenced by abnormal lipid metabolism, insulin resistance, and dysbiosis. In conclusion, deciphering the intricate interactions among metabolic processes, genetic predispositions, inflammatory responses, immune regulation, and microbial ecology is imperative for the development of novel therapeutic and preventative measures against metabolic-associated HCC.

Publication History

Accepted Manuscript online:
18 March 2024

Article published online:
18 April 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

• References

• 1 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
  Google Scholar
• 2 Llovet JM, Kelley RK, Villanueva A. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7 (01) 6
  CrossrefPubMedGoogle Scholar
• 3 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 (04) 223-238
  CrossrefPubMedGoogle Scholar
• 4 Llovet JM, Willoughby CE, Singal AG. et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol 2023; 20 (08) 487-503
  CrossrefPubMedGoogle Scholar
• 5 Rinella ME, Lazarus JV, Ratziu V. et al; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023; 79 (06) 1542-1556
  CrossrefPubMedGoogle Scholar
• 6 Kucukoglu O, Sowa JP, Mazzolini GD, Syn WK, Canbay A. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol 2021; 74 (02) 442-457
  CrossrefPubMedGoogle Scholar
• 7 Tokushige K. New concept in fatty liver diseases. Hepatol Res 2024; 54 (02) 125-130
  CrossrefPubMedGoogle Scholar
• 8 Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol 2024; 80 (02) e76-e77
  CrossrefPubMedGoogle Scholar
• 9 Song SJ, Lai JC, Wong GL, Wong VW, Yip TC. Can we use old NAFLD data under the new MASLD definition?. J Hepatol 2024; 80 (02) e54-e56
  CrossrefPubMedGoogle Scholar
• 10 Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019; 16 (07) 411-428
  CrossrefPubMedGoogle Scholar
• 11 Le MH, Yeo YH, Zou B. et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical Bayesian approach. Clin Mol Hepatol 2022; 28 (04) 841-850
  CrossrefPubMedGoogle Scholar
• 12 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
  CrossrefPubMedGoogle Scholar
• 13 Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009; 24 (02) 248-254
  CrossrefPubMedGoogle Scholar
• 14 Younossi Z, Stepanova M, Ong JP. et al; Global Nonalcoholic Steatohepatitis Council. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol 2019; 17 (04) 748-755.e3
  CrossrefPubMedGoogle Scholar
• 15 Dyson J, Jaques B, Chattopadyhay D. et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60 (01) 110-117
  CrossrefPubMedGoogle Scholar
• 16 Pais R, Fartoux L, Goumard C. et al. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. Aliment Pharmacol Ther 2017; 46 (09) 856-863
  CrossrefPubMedGoogle Scholar
• 17 Tateishi R, Uchino K, Fujiwara N. et al. A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update. J Gastroenterol 2019; 54 (04) 367-376
  CrossrefPubMedGoogle Scholar
• 18 Ertle J, Dechêne A, Sowa JP. et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011; 128 (10) 2436-2443
  CrossrefPubMedGoogle Scholar
• 19 Chayanupatkul M, Omino R, Mittal S. et al. Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection. J Hepatol 2017; 66 (02) 355-362
  CrossrefPubMedGoogle Scholar
• 20 Zunica ERM, Heintz EC, Axelrod CL, Kirwan JP. Obesity management in the primary prevention of hepatocellular carcinoma. Cancers (Basel) 2022; 14 (16) 14
  CrossrefPubMedGoogle Scholar
• 21 Ward ZJ, Bleich SN, Cradock AL. et al. Projected U.S. state-level prevalence of adult obesity and severe obesity. N Engl J Med 2019; 381 (25) 2440-2450
  CrossrefPubMedGoogle Scholar
• 22 Park EJ, Lee JH, Yu GY. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140 (02) 197-208
  CrossrefPubMedGoogle Scholar
• 23 Sohn W, Lee HW, Lee S. et al. Obesity and the risk of primary liver cancer: a systematic review and meta-analysis. Clin Mol Hepatol 2021; 27 (01) 157-174
  CrossrefPubMedGoogle Scholar
• 24 Yan LJ, Yang LS, Yan YC. et al. Anthropometric indicators of adiposity and risk of primary liver cancer: a systematic review and dose-response meta-analysis. Eur J Cancer 2023; 185: 150-163
  CrossrefPubMedGoogle Scholar
• 25 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 (03) 808-819
  CrossrefPubMedGoogle Scholar
• 26 Kanwal F, Kramer JR, Mapakshi S. et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018; 155 (06) 1828-1837.e2
  CrossrefPubMedGoogle Scholar
• 27 Rustgi VK, Li Y, Gupta K. et al. Bariatric surgery reduces cancer risk in adults with nonalcoholic fatty liver disease and severe obesity. Gastroenterology 2021; 161 (01) 171-184.e10
  CrossrefPubMedGoogle Scholar
• 28 Li X, Wang X, Gao P. Diabetes mellitus and risk of hepatocellular carcinoma. BioMed Res Int 2017; 2017: 5202684
  PubMedGoogle Scholar
• 29 Yang JD, Ahmed F, Mara KC. et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology 2020; 71 (03) 907-916
  CrossrefPubMedGoogle Scholar
• 30 Alexander M, Loomis AK, van der Lei J. et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med 2019; 17 (01) 95
  CrossrefPubMedGoogle Scholar
• 31 Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci 2018; 109 (05) 1282-1291
  CrossrefPubMedGoogle Scholar
• 32 Rudolph KL, Hartmann D, Opitz OG. Telomere dysfunction and DNA damage checkpoints in diseases and cancer of the gastrointestinal tract. Gastroenterology 2009; 137 (03) 754-762
  CrossrefPubMedGoogle Scholar
• 33 Nault JC, Calderaro J, Di Tommaso L. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 2014; 60 (06) 1983-1992
  CrossrefPubMedGoogle Scholar
• 34 Pinyol R, Torrecilla S, Wang H. et al. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2021; 75 (04) 865-878
  CrossrefPubMedGoogle Scholar
• 35 Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest 2022; 132 (04) 132
  CrossrefPubMedGoogle Scholar
• 36 Schulze K, Imbeaud S, Letouzé E. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015; 47 (05) 505-511
  CrossrefPubMedGoogle Scholar
• 37 Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell 2017; 169: 1327-1341.e23
  CrossrefPubMedGoogle Scholar
• 38 Murai H, Kodama T, Maesaka K. et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology 2023; 77 (01) 77-91
  CrossrefPubMedGoogle Scholar
• 39 BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017; 66 (04) 1111-1124
  CrossrefPubMedGoogle Scholar
• 40 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 (19) 9521-9526
  CrossrefPubMedGoogle Scholar
• 41 Anstee QM, Darlay R, Cockell S. et al; EPoS Consortium Investigators. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort^☆ . J Hepatol 2020; 73 (03) 505-515
  CrossrefPubMedGoogle Scholar
• 42 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 (01) 75-81
  CrossrefPubMedGoogle Scholar
• 43 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 (04) 352-356
  CrossrefPubMedGoogle Scholar
• 44 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
  CrossrefPubMedGoogle Scholar
• 45 Perez-Martinez P, Delgado-Lista J, Garcia-Rios A. et al. Glucokinase regulatory protein genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome. PLoS ONE 2011; 6 (06) e20555
  CrossrefPubMedGoogle Scholar
• 46 Kimura M, Iguchi T, Iwasawa K. et al. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell 2022; 185 (22) 4216-4232.e16
  CrossrefPubMedGoogle Scholar
• 47 Tan HL, Zain SM, Mohamed R. et al. Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. J Gastroenterol 2014; 49 (06) 1056-1064
  CrossrefPubMedGoogle Scholar
• 48 Kawaguchi T, Shima T, Mizuno M. et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS ONE 2018; 13 (01) e0185490
  CrossrefPubMedGoogle Scholar
• 49 Mancina RM, Dongiovanni P, Petta S. et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 2016; 150 (05) 1219-1230.e6
  CrossrefPubMedGoogle Scholar
• 50 Donati B, Dongiovanni P, Romeo S. et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep 2017; 7 (01) 4492
  CrossrefPubMedGoogle Scholar
• 51 Tepper CG, Dang JHT, Stewart SL. et al. High frequency of the PNPLA3 rs738409 [G] single-nucleotide polymorphism in Hmong individuals as a potential basis for a predisposition to chronic liver disease. Cancer 2018; 124 (Suppl. 07) 1583-1589
  CrossrefPubMedGoogle Scholar
• 52 Riazi K, Swain MG, Congly SE, Kaplan GG, Shaheen AA. Race and ethnicity in non-alcoholic fatty liver disease (NAFLD): a narrative review. Nutrients 2022; 14 (21) 14
  CrossrefPubMedGoogle Scholar
• 53 Hassan MM, Li D, Han Y. et al. Genome-wide association study identifies high-impact susceptibility loci for hepatocellular carcinoma in North America. Hepatology 2024; (e-pub ahead of print). DOI: 10.1097/hep.0000000000000800.
  CrossrefPubMedGoogle Scholar
• 54 El Jabbour T, Lagana SM, Lee H. Update on hepatocellular carcinoma: pathologists' review. World J Gastroenterol 2019; 25 (14) 1653-1665
  CrossrefPubMedGoogle Scholar
• 55 Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: the growing challenge. Hepatology 2023; 77 (01) 323-338
  CrossrefPubMedGoogle Scholar
• 56 Yang YM, Kim SY, Seki E. Inflammation and liver cancer: molecular mechanisms and therapeutic targets. Semin Liver Dis 2019; 39 (01) 26-42
  Article in Thieme ConnectPubMedGoogle Scholar
• 57 Luedde T, Schwabe RF. NF-κB in the liver–linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8 (02) 108-118
  CrossrefPubMedGoogle Scholar
• 58 He G, Karin M. NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res 2011; 21 (01) 159-168
  CrossrefPubMedGoogle Scholar
• 59 Grohmann M, Wiede F, Dodd GT. et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 2018; 175 (05) 1289-1306.e20
  CrossrefPubMedGoogle Scholar
• 60 Litwak SA, Pang L, Galic S. et al. JNK activation of BIM promotes hepatic oxidative stress, steatosis, and insulin resistance in obesity. Diabetes 2017; 66 (12) 2973-2986
  CrossrefPubMedGoogle Scholar
• 61 Das M, Garlick DS, Greiner DL, Davis RJ. The role of JNK in the development of hepatocellular carcinoma. Genes Dev 2011; 25 (06) 634-645
  CrossrefPubMedGoogle Scholar
• 62 Portincasa P, Bonfrate L, Khalil M. et al. Intestinal barrier and permeability in health, obesity and NAFLD. Biomedicines 2021; 10 (01) 10
  CrossrefPubMedGoogle Scholar
• 63 Heymann F, Tacke F. Immunology in the liver–from homeostasis to disease. Nat Rev Gastroenterol Hepatol 2016; 13 (02) 88-110
  CrossrefPubMedGoogle Scholar
• 64 Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol 2018; 15 (06) 349-364
  CrossrefPubMedGoogle Scholar
• 65 Xiong X, Kuang H, Ansari S. et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol Cell 2019; 75 (03) 644-660.e5
  CrossrefPubMedGoogle Scholar
• 66 Daemen S, Gainullina A, Kalugotla G. et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep 2021; 34 (02) 108626
  CrossrefPubMedGoogle Scholar
• 67 Seidman JS, Troutman TD, Sakai M. et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity 2020; 52 (06) 1057-1074.e7
  CrossrefPubMedGoogle Scholar
• 68 Hwang S, Yun H, Moon S, Cho YE, Gao B. Role of neutrophils in the pathogenesis of nonalcoholic steatohepatitis. Front Endocrinol (Lausanne) 2021; 12: 751802
  CrossrefPubMedGoogle Scholar
• 69 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 (04) 1347-1360
  CrossrefPubMedGoogle Scholar
• 70 Leslie J, Mackey JBG, Jamieson T. et al. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut 2022; 71 (10) 2093-2106
  CrossrefPubMedGoogle Scholar
• 71 Wang H, Zhang H, Wang Y. et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol 2021; 75 (06) 1271-1283
  CrossrefPubMedGoogle Scholar
• 72 Ostrand-Rosenberg S, Fenselau C. Myeloid-derived suppressor cells: immune-suppressive cells that impair antitumor immunity and are sculpted by their environment. J Immunol 2018; 200 (02) 422-431
  CrossrefPubMedGoogle Scholar
• 73 Tang W, Zhou J, Yang W. et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol 2022; 19 (07) 834-847
  CrossrefPubMedGoogle Scholar
• 74 Sutti S, Jindal A, Locatelli I. et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 2014; 59 (03) 886-897
  CrossrefPubMedGoogle Scholar
• 75 Luo XY, Takahara T, Kawai K. et al. IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet. Am J Physiol Gastrointest Liver Physiol 2013; 305 (12) G891-G899
  CrossrefPubMedGoogle Scholar
• 76 Moreno-Fernandez ME, Giles DA, Oates JR. et al. PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab 2021; 33 (06) 1187-1204.e9
  CrossrefPubMedGoogle Scholar
• 77 Ma C, Kesarwala AH, Eggert T. et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531 (7593) 253-257
  CrossrefPubMedGoogle Scholar
• 78 Gomes AL, Teijeiro A, Burén S. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 2016; 30 (01) 161-175
  CrossrefPubMedGoogle Scholar
• 79 Dudek M, Pfister D, Donakonda S. et al. Auto-aggressive CXCR6⁺ CD8 T cells cause liver immune pathology in NASH. Nature 2021; 592 (7854) 444-449
  CrossrefPubMedGoogle Scholar
• 80 Koda Y, Teratani T, Chu PS. et al. CD8⁺ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat Commun 2021; 12 (01) 4474
  CrossrefPubMedGoogle Scholar
• 81 Pfister D, Núñez NG, Pinyol R. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021; 592 (7854) 450-456
  CrossrefPubMedGoogle Scholar
• 82 Shalapour S, Lin XJ, Bastian IN. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017; 551 (7680) 340-345
  CrossrefPubMedGoogle Scholar
• 83 Bruzzì S, Sutti S, Giudici G. et al. B2-lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD). Free Radic Biol Med 2018; 124: 249-259
  CrossrefPubMedGoogle Scholar
• 84 Barrow F, Khan S, Fredrickson G. et al. Microbiota-driven activation of intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology 2021; 74 (02) 704-722
  CrossrefPubMedGoogle Scholar
• 85 Thapa M, Chinnadurai R, Velazquez VM. et al. Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology 2015; 61 (06) 2067-2079
  CrossrefPubMedGoogle Scholar
• 86 Novobrantseva TI, Majeau GR, Amatucci A. et al. Attenuated liver fibrosis in the absence of B cells. J Clin Invest 2005; 115 (11) 3072-3082
  CrossrefPubMedGoogle Scholar
• 87 Faggioli F, Palagano E, Di Tommaso L. et al. B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury. Hepatology 2018; 67 (05) 1970-1985
  CrossrefPubMedGoogle Scholar
• 88 Zhang S, Liu Z, Wu D, Chen L, Xie L. Single-cell RNA-seq analysis reveals microenvironmental infiltration of plasma cells and hepatocytic prognostic markers in HCC with cirrhosis. Front Oncol 2020; 10: 596318
  CrossrefPubMedGoogle Scholar
• 89 Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 2012; 21 (03) 297-308
  CrossrefPubMedGoogle Scholar
• 90 Sunami Y, Rebelo A, Kleeff J. Lipid metabolism and lipid droplets in pancreatic cancer and stellate cells. Cancers (Basel) 2017; 10 (01) 10
  CrossrefPubMedGoogle Scholar
• 91 Budhu A, Roessler S, Zhao X. et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology 2013; 144 (05) 1066-1075.e1
  CrossrefPubMedGoogle Scholar
• 92 Sunami Y. NASH, fibrosis and hepatocellular carcinoma: lipid synthesis and glutamine/acetate signaling. Int J Mol Sci 2020; 21 (18) 21
  CrossrefPubMedGoogle Scholar
• 93 Esler WP, Cohen DE. Pharmacologic inhibition of lipogenesis for the treatment of NAFLD. J Hepatol 2024; 80 (02) 362-377
  CrossrefPubMedGoogle Scholar
• 94 Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 2014; 146 (03) 726-735
  CrossrefPubMedGoogle Scholar
• 95 Icard P, Wu Z, Fournel L, Coquerel A, Lincet H, Alifano M. ATP citrate lyase: a central metabolic enzyme in cancer. Cancer Lett 2020; 471: 125-134
  CrossrefPubMedGoogle Scholar
• 96 Baenke F, Peck B, Miess H, Schulze A. Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech 2013; 6 (06) 1353-1363
  CrossrefPubMedGoogle Scholar
• 97 Calvisi DF, Wang C, Ho C. et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 2011; 140 (03) 1071-1083
  CrossrefPubMedGoogle Scholar
• 98 Li L, Pilo GM, Li X. et al. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J Hepatol 2016; 64 (02) 333-341
  CrossrefPubMedGoogle Scholar
• 99 Che L, Chi W, Qiao Y. et al. Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut 2020; 69 (01) 177-186
  CrossrefPubMedGoogle Scholar
• 100 Lally JSV, Ghoshal S, DePeralta DK. et al. Inhibition of Acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab 2019; 29 (01) 174-182.e5
  CrossrefPubMedGoogle Scholar
• 101 Dhanasekaran R, Suzuki H, Lemaitre L, Kubota N, Hoshida Y. Molecular and immune landscape of hepatocellular carcinoma to guide therapeutic decision-making. Hepatology 2023; (e-pub ahead of print). DOI: 10.1097/hep.0000000000000513.
  CrossrefPubMedGoogle Scholar
• 102 Kotronen A, Seppänen-Laakso T, Westerbacka J. et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes 2009; 58 (01) 203-208
  CrossrefPubMedGoogle Scholar
• 103 Yamashita T, Honda M, Takatori H. et al. Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J Hepatol 2009; 50 (01) 100-110
  CrossrefPubMedGoogle Scholar
• 104 Li C, Yang W, Zhang J. et al. SREBP-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma. Int J Mol Sci 2014; 15 (05) 7124-7138
  CrossrefPubMedGoogle Scholar
• 105 Régnier M, Carbinatti T, Parlati L, Benhamed F, Postic C. The role of ChREBP in carbohydrate sensing and NAFLD development. Nat Rev Endocrinol 2023; 19 (06) 336-349
  CrossrefPubMedGoogle Scholar
• 106 Lee SH, Lee JH, Im SS. The cellular function of SCAP in metabolic signaling. Exp Mol Med 2020; 52 (05) 724-729
  CrossrefPubMedGoogle Scholar
• 107 Kawamura S, Matsushita Y, Kurosaki S. et al. Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis. J Clin Invest 2022; 132 (11) 132
  CrossrefPubMedGoogle Scholar
• 108 Zhu L, Baker SS, Liu W. et al. Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. Metabolism 2011; 60 (07) 1001-1011
  CrossrefPubMedGoogle Scholar
• 109 Greco D, Kotronen A, Westerbacka J. et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294 (05) G1281-G1287
  CrossrefPubMedGoogle Scholar
• 110 Nath A, Li I, Roberts LR, Chan C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci Rep 2015; 5: 14752
  CrossrefPubMedGoogle Scholar
• 111 Westerbacka J, Kolak M, Kiviluoto T. et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 2007; 56 (11) 2759-2765
  CrossrefPubMedGoogle Scholar
• 112 Higuchi N, Kato M, Tanaka M. et al. Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease. Exp Ther Med 2011; 2 (06) 1077-1081
  CrossrefPubMedGoogle Scholar
• 113 Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 2012; 485 (7400) 661-665
  CrossrefPubMedGoogle Scholar
• 114 Yuan H, Wen B, Liu X. et al. CCAAT/enhancer-binding protein α is required for hepatic outgrowth via the p53 pathway in zebrafish. Sci Rep 2015; 5: 15838
  CrossrefPubMedGoogle Scholar
• 115 Fang C, Pan J, Qu N. et al. The AMPK pathway in fatty liver disease. Front Physiol 2022; 13: 970292
  CrossrefPubMedGoogle Scholar
• 116 Iwamoto H, Abe M, Yang Y. et al. Cancer lipid metabolism confers antiangiogenic drug resistance. Cell Metab 2018; 28 (01) 104-117.e5
  CrossrefPubMedGoogle Scholar
• 117 Huang D, Li T, Li X. et al. HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 2014; 8 (06) 1930-1942
  CrossrefPubMedGoogle Scholar
• 118 Zhang J, Liu Z, Lian Z. et al. Monoacylglycerol lipase: a novel potential therapeutic target and prognostic indicator for hepatocellular carcinoma. Sci Rep 2016; 6: 35784
  CrossrefPubMedGoogle Scholar
• 119 Cao D, Song X, Che L. et al. Both de novo synthetized and exogenous fatty acids support the growth of hepatocellular carcinoma cells. Liver Int 2017; 37 (01) 80-89
  CrossrefPubMedGoogle Scholar
• 120 Shao G, Liu Y, Lu L. et al. The pathogenesis of HCC driven by NASH and the preventive and therapeutic effects of natural products. Front Pharmacol 2022; 13: 944088
  CrossrefPubMedGoogle Scholar
• 121 Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR. Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology 1997; 26 (03) 598-604
  CrossrefPubMedGoogle Scholar
• 122 Rajesh Y, Sarkar D. Molecular mechanisms regulating obesity-associated hepatocellular carcinoma. Cancers (Basel) 2020; 12 (05) 12
  CrossrefPubMedGoogle Scholar
• 123 Shiode Y, Kodama T, Shigeno S. et al. TNF receptor-related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF-κB-inducing kinase-mediated hepatocyte transdifferentiation. Hepatology 2023; 77 (02) 395-410
  CrossrefPubMedGoogle Scholar
• 124 Kodama T, Yi J, Newberg JY. et al. Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis. Proc Natl Acad Sci U S A 2018; 115 (44) E10417-E10426
  CrossrefPubMedGoogle Scholar
• 125 Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol 2017; 13 (12) 710-730
  CrossrefPubMedGoogle Scholar
• 126 Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008; 118 (03) 829-838
  CrossrefPubMedGoogle Scholar
• 127 Kaji K, Yoshiji H, Kitade M. et al. Impact of insulin resistance on the progression of chronic liver diseases. Int J Mol Med 2008; 22 (06) 801-808
  PubMedGoogle Scholar
• 128 Cai W, Ma Y, Song L. et al. IGF-1R down regulates the sensitivity of hepatocellular carcinoma to sorafenib through the PI3K/akt and RAS/raf/ERK signaling pathways. BMC Cancer 2023; 23 (01) 87
  CrossrefPubMedGoogle Scholar
• 129 Fan W, Adebowale K, Váncza L. et al. Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver. Nature 2024; 626 (7999) 635-642
  CrossrefPubMedGoogle Scholar
• 130 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 (01) 107-120
  CrossrefPubMedGoogle Scholar
• 131 Liakina V, Strainiene S, Stundiene I, Maksimaityte V, Kazenaite E. Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis. World J Hepatol 2022; 14 (07) 1277-1290
  CrossrefPubMedGoogle Scholar
• 132 Yoshimoto S, Loo TM, Atarashi K. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456) 97-101
  CrossrefPubMedGoogle Scholar
• 133 Yamagishi R, Kamachi F, Nakamura M. et al. Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma. Sci Immunol 2022; 7 (72) eabl7209
  CrossrefPubMedGoogle Scholar
• 134 Loo TM, Kamachi F, Watanabe Y. et al. Gut microbiota promotes obesity-associated liver cancer through PGE₂-mediated suppression of antitumor immunity. Cancer Discov 2017; 7 (05) 522-538
  CrossrefPubMedGoogle Scholar
• 135 Gäbele E, Mühlbauer M, Dorn C. et al. Role of TLR9 in hepatic stellate cells and experimental liver fibrosis. Biochem Biophys Res Commun 2008; 376 (02) 271-276
  CrossrefPubMedGoogle Scholar