Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma

Sana Raza, Sangam Rajak, Baby Anjum, Rohit A Sinha, Sana Raza, Sangam Rajak, Baby Anjum, Rohit A Sinha

Abstract

Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.

Keywords: ER-stress; Gut microbiome; Non-alcoholic fatty liver disease; ROS; TLR-4; TLR-9; TNFα; autophagy; dysbiosis; hepatocellular carcinoma; hyperinsulinemia; non-alcoholic steatohepatitis.

Conflict of interest statement

Conflicts of interest All authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Multiple hits lead to onset and progression of NAFLD/NASH to HCC. Diverse signalling pathways involved in metabolic stress such as FFAs ER-stress, cytokine production (IL-6, IL-17, IL-11 and TGF-β), altered immune response, pro-fibrogenic mediators (hedgehog and NF-κB), gut dysbiosis and endocrine defects drive the development of NAFLD/NASH-associated HCC. NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; HCC: hepatocellular carcinoma; FFAs: free fatty acids; ER: endoplasmic reticulum; IL-6: interleukin-6; IL-17: interleukin-17; IL-11: interleukin-11; TGF-β: transforming growth factor β; SNPs: single nucleotide polymorphisms; miRNA: micro RNA; PI3K: phosphatidylinositol 3-kinases; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B-cells; TNF-α: tumour necrosis factor-alpha; ERK: extracellular receptor kinase; JAK: Janus kinase; STAT: signal transducer and activator of transcription

References

    1. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, et al. Global Burden of Disease Liver Cancer Collaboration. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3:1683–91.
    1. Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol. 2010;16:3603–15.
    1. Bertot LC, Adams LA. Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2019;13:179–87.
    1. Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378:804–14.
    1. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20.
    1. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, et al. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet. 2014;384:755–65.
    1. Milic S, Lulic D, Stimac D. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations. World J Gastroenterol. 2014;20:9330–7.
    1. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67:862–73.
    1. Petrucciani N, Gugenheim J. Molecular pathways between obesity, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) Hepatobiliary Surg Nutr. 2019;8:395–7.
    1. Xia MF, Bian H, Gao X. NAFLD and diabetes: two sides of the same coin? Rationale for gene-based personalized NAFLD treatment. Front Pharmacol. 2019;10:877.
    1. Masarone M, Rosato V, Aglitti A, Bucci T, Caruso R, et al. Liver biopsy in type 2 diabetes mellitus: steatohepatitis represents the sole feature of liver damage. PLoS One. 2017;12:e0178473.
    1. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care. 2017;40:419–30.
    1. Mantovani A, Targher G. Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease. Ann Transl Med. 2017;5:270.
    1. Agosti P, Sabba C, Mazzocca A. Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment. Biochim Biophys Acta Mol Basis Dis. 2018;1864:607–17.
    1. Yang JD, Ahmed F, Mara KC, Addissie BD, Allen AM, et al. Diabetes is associated with increased risk of hepatocellular carcinoma in cirrhosis patients with nonalcoholic fatty liver disease. Hepatology. 2019 doi: 10.1002/hep.30858. Epub ahead of print.
    1. Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 2016;36:317–24.
    1. Younossi Z, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol. 2019;17:748–55.e3.
    1. Reig M, Gambato M, Man NK, Roberts JP, Victor D, et al. Should patients with NAFLD/NASH be surveyed for HCC? Transplantation. 2019;103:39–44.
    1. Sadler EM, Mehta N, Bhat M, Ghanekar A, Greig PD, et al. Liver transplantation for NASH-related hepatocellular carcinoma versus non-NASH etiologies of hepatocellular carcinoma. Transplantation. 2018;102:640–7.
    1. Olofson AM, Gonzalo DH, Chang M, Liu X. Steatohepatitic variant of hepatocellular carcinoma: a focused review. Gastroenterology Res. 2018;11:391–6.
    1. Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155:1828–37.e2.
    1. Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol. 2018;69:896–904.
    1. Uygun A. Is that possible to stop or cease the NASH to turn into HCC? J Gastrointest Cancer. 2017;48:250–5.
    1. Yopp AC, Choti MA. Non-alcoholic steatohepatitis-related hepatocellular carcinoma: a growing epidemic? Dig Dis. 2015;33:642–7.
    1. Weinmann A, Alt Y, Koch S, Nelles C, Duber C, et al. Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma. BMC Cancer. 2015;15:210.
    1. Oda K, Uto H, Mawatari S, Ido A. Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: a review of human studies. Clin J Gastroenterol. 2015;8:1–9.
    1. Page JM, Harrison SA. NASH and HCC. Clin Liver Dis. 2009;13:631–47.
    1. Zen Y, Katayanagi K, Tsuneyama K, Harada K, Araki I, et al. Hepatocellular carcinoma arising in non-alcoholic steatohepatitis. Pathol Int. 2001;51:127–31.
    1. Gawrieh S, Dakhoul L, Miller E, Scanga A, deLemos A, et al. Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study. Aliment Pharmacol Ther. 2019;50:809–21.
    1. Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell. 2018;175:1289–306.e20.
    1. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62:1723–30.
    1. Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63:827–38.
    1. Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:428–33.
    1. Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. 2011;128:2436–43.
    1. Chen K, Ma J, Jia X, Ai W, Ma Z, et al. Advancing the understanding of NAFLD to hepatocellular carcinoma development: From experimental models to humans. Biochim Biophys Acta Rev Cancer. 2019;1871:117–25.
    1. Anstee QM, Day CP. The genetics of nonalcoholic fatty liver disease: spotlight on PNPLA3 and TM6SF2. Semin Liver Dis. 2015;35:270–90.
    1. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) Metabolism. 2016;65:1038–48.
    1. Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci. 2019;76:99–128.
    1. Spahis S, Delvin E, Borys JM, Levy E. Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis. Antioxid Redox Signal. 2017;26:519–41.
    1. Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20:1768–76.
    1. Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C, et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393–405.
    1. Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018;67:1270–83.
    1. 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.
    1. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109:325–34.
    1. Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, 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.
    1. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46:352–6.
    1. Chen LZ, Xia HH, Xin YN, Lin ZH, Xuan SY. TM6SF2 E167K variant, a novel genetic susceptibility variant, contributing to nonalcoholic fatty liver disease. J Clin Transl Hepatol. 2015;3:265–70.
    1. Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7 4492.
    1. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.
    1. Tryndyak VP, Han T, Muskhelishvili L, Fuscoe JC, Ross SA, et al. Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl-deficient diet. Mol Nutr Food Res. 2011;55:411–8.
    1. Liu F, Li H, Chang H, Wang J, Lu J. Identification of hepatocellular carcinoma-associated hub genes and pathways by integrated microarray analysis. Tumori. 2015;101:206–14.
    1. Erstad DJ, Fuchs BC, Tanabe KK. Molecular signatures in hepatocellular carcinoma: a step toward rationally designed cancer therapy. Cancer. 2018;124:3084–104.
    1. de Conti A, Ortega JF, Tryndyak V, Dreval K, Moreno FS, et al. MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis. Oncotarget. 2017;8:88517–28.
    1. Xu Z, Hu J, Cao H, Pilo MG, Cigliano A, et al. Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway. Exp Mol Med. 2018;50:e417.
    1. Tessitore A, Cicciarelli G, Del Vecchio F, Gaggiano A, Verzella D, et al. MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice. BMC Cancer. 2016;16:3.
    1. Takakura K, Oikawa T, Nakano M, Saeki C, Torisu Y, et al. Recent insights into the multiple pathways driving non-alcoholic steatohepatitis-derived hepatocellular carcinoma. Front Oncol. 2019;9:762.
    1. Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 2019;16:411–28.
    1. Grattagliano I, de Bari O, Bernardo TC, Oliveira PJ, Wang DQ, et al. Role of mitochondria in nonalcoholic fatty liver disease - from origin to propagation. Clin Biochem. 2012;45:610–8.
    1. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.
    1. Nakagawa H, Hayata Y, Kawamura S, Yamada T, Fujiwara N, et al. Lipid metabolic reprogramming in hepatocellular carcinoma. Cancers (Basel) 2018;10:E447.
    1. Hirsova P, Ibrahim SH, Gores GJ, Malhi H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res. 2016;57:1758–70.
    1. Garcia-Ruiz C, Fernandez-Checa JC. Mitochondrial oxidative stress and antioxidants balance in fatty liver disease. Hepatol Commun. 2018;2:1425–39.
    1. Masarone M, Rosato V, Dallio M, Gravina AG, Aglitti A, et al. Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2018;2018 9547613.
    1. Fu Y, Chung FL. Oxidative stress and hepatocarcinogenesis. Hepatoma Res. 2018;4
    1. Nishida N, Yada N, Hagiwara S, Sakurai T, Kitano M, et al. Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2016;31:1646–53.
    1. Song MJ, Malhi H. The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharmacol Ther. 2019;203 107401.
    1. Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26:331–43.
    1. Wu WKK, Zhang L, Chan MTV. Autophagy, NAFLD and NAFLD-related HCC. Adv Exp Med Biol. 2018;1061:127–38.
    1. Tian Y, Yang B, Qiu W, Hao Y, Zhang Z, et al. ER-residential Nogo-B accelerates NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy. Nat Commun. 2019;10 3391.
    1. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 2013;51:618–31.
    1. Sinha RA, Singh BK, Zhou J, Wu Y, Farah BL, et al. Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling. Autophagy. 2015;11:1341–57.
    1. Sinha RA, Sun K, Xu L, Jing Y, Han Z, Chen X, et al. Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-kappaB-IL1alpha/beta-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. Cancer Lett. 2017;388:198–207.
    1. Kanno M, Kawaguchi K, Honda M, Horii R, Takatori H, et al. Serum aldo-keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis. J Gastroenterol. 2019;54:549–57.
    1. Arendt BM, Teterina A, Pettinelli P, Comelli EM, Ma DWL, et al. Cancer-related gene expression is associated with disease severity and modifiable lifestyle factors in non-alcoholic fatty liver disease. Nutrition. 2019;62:100–7.
    1. Torres-Mena JE, Salazar-Villegas KN, Sanchez-Rodriguez R, Lopez-Gabino B, Del Pozo-Yauner L, et al. Aldo-Keto reductases as early biomarkers of hepatocellular carcinoma: a comparison between animal models and human HCC. Dig Dis Sci. 2018;63:934–44.
    1. Nikolaou N, Gathercole LL, Marchand L, Althari S, Dempster NJ, et al. AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease. Metabolism. 2019;99:67–80.
    1. Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68:280–95.
    1. Iannucci LF, Sun J, Singh BK, Zhou J, Kaddai VA, et al. Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells. Biochem Biophys Res Commun. 2016;480:461–7.
    1. Koopman N, Molinaro A, Nieuwdorp M, Holleboom AG. Review article: can bugs be drugs? The potential of probiotics and prebiotics as treatment for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2019;50:628–39.
    1. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, et al. Role of the normal gut microbiota. World J Gastroenterol. 2015;21:8787–803.
    1. Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol. 2019;71:1216–28.
    1. Liu Q, Liu S, Chen L, Zhao Z, Du S, et al. Role and effective therapeutic target of gut microbiota in NAFLD/NASH. Exp Ther Med. 2019;18:1935–44.
    1. Kim HN, Joo EJ, Cheong HS, Kim Y, Kim HL, et al. Gut microbiota and risk of persistent nonalcoholic fatty liver diseases. J Clin Med. 2019;8:E1089.
    1. Jasirwan COM, Lesmana CRA, Hasan I, Sulaiman AS, Gani RA. The role of gut microbiota in non-alcoholic fatty liver disease: pathways of mechanisms. Biosci Microbiota Food Health. 2019;38:81–8.
    1. Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol. 2016;13:412–25.
    1. Ezzaidi N, Zhang X, Coker OO, Yu J. New insights and therapeutic implication of gut microbiota in non-alcoholic fatty liver disease and its associated liver cancer. Cancer Lett. 2019;459:186–91.
    1. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101.
    1. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504–16.
    1. Chu H, Williams B, Schnabl B. Gut microbiota, fatty liver disease, and hepatocellular carcinoma. Liver Res. 2018;2:43–51.
    1. Nguyen J, Jiao J, Smoot K, Watt GP, Zhao C, et al. Toll-like receptor 4: a target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis. Oncotarget. 2018;9:29495–507.
    1. Liu Y, Yan W, Tohme S, Chen M, Fu Y, et al. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J Hepatol. 2015;63:114–21.
    1. Brandi G, De Lorenzo S, Candela M, Pantaleo MA, Bellentani S, et al. Microbiota, NASH, HCC and the potential role of probiotics. Carcinogenesis. 2017;38:231–40.
    1. Takahashi S, Tanaka N, Fukami T, Xie C, Yagai T, et al. Role of farnesoid X receptor and bile acids in hepatic tumor development. Hepatol Commun. 2018;2:1567–82.
    1. He G, Karin M. NF-kappa B and STAT3 - key players in liver inflammation and cancer. Cell Res. 2011;21:159–68.
    1. Park EJ, Lee JH, Yu GY, He G, Ali SR, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.
    1. Min HK, Mirshahi F, Verdianelli A, Pacana T, Patel V, et al. Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2015;308:G794–803.
    1. Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis. Gastroenterology. 2019;157:777–92.e14.
    1. Zheng H, Yang Y, Han J, Jiang WH, Chen C, et al. TMED3 promotes hepatocellular carcinoma progression via IL-11/STAT3 signaling. Sci Rep. 2016;6 37070.
    1. Gomes AL, Teijeiro A, Buren S, Tummala KS, Yilmaz M, et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2016;30:161–75.
    1. Syn WK, Choi SS, Liaskou E, Karaca GF, Agboola KM, et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 2011;53:106–15.
    1. Chung SI, Moon H, Ju HL, Cho KJ, Kim DY, et al. Hepatic expression of sonic hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J Hepatol. 2016;64:618–27.
    1. Chen J, Gingold JA, Su X. Immunomodulatory TGF-beta signaling in hepatocellular carcinoma. Trends Mol Med. 2019;25:1010–23.
    1. Yang L, Roh YS, Song J, Zhang B, Liu C, et al. Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology. 2014;59:483–95.
    1. Jin Z, Lei L, Lin D, Liu Y, Song Y, et al. IL-33 released in the liver inhibits tumor growth via promotion of CD4(+) and CD8(+) T cell responses in hepatocellular carcinoma. J Immunol. 2018;201:3770–9.
    1. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7.
    1. Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, et al. Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med. 2019;25:641–55.
    1. de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, et al. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2019;70:710–21.
    1. Bril F, Lomonaco R, Orsak B, Ortiz-Lopez C, Webb A, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology. 2014;59:2178–87.
    1. De Minicis S, Agostinelli L, Rychlicki C, Sorice GP, Saccomanno S, et al. HCC development is associated to peripheral insulin resistance in a mouse model of NASH. PLoS One. 2014;9:e97136.
    1. Kudo Y, Tanaka Y, Tateishi K, Yamamoto K, Yamamoto S, et al. Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway. J Hepatol. 2011;55:1400–8.
    1. Jeong SH, Kim HB, Kim MC, Lee JM, Lee JH, et al. Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. J Clin Invest. 2018;128:1010–25.
    1. Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35:2203–17.
    1. Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, et al. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia. 2016;59:30–43.
    1. Jiang N, Sun R, Sun Q. Leptin signaling molecular actions and drug target in hepatocellular carcinoma. Drug Des Devel Ther. 2014;8:2295–302.
    1. Stefanou N, Papanikolaou V, Furukawa Y, Nakamura Y, Tsezou A. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase. BMC Cancer. 2010;10:442.
    1. Bruinstroop E, Dalan R, Cao Y, Bee YM, Chandran K, et al. Low-dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. J Clin Endocrinol Metab. 2018;103:2698–706.
    1. Pinter M, Haupt L, Hucke F, Bota S, Bucsics T, et al. The impact of thyroid hormones on patients with hepatocellular carcinoma. PLoS One. 2017;12:e0181878.
    1. Lonardo A, Ballestri S, Mantovani A, Nascimbeni F, Lugari S, et al. Pathogenesis of hypothyroidism-induced NAFLD: evidence for a distinct disease entity? Dig Liver Dis. 2019;51:462–70.
    1. Sinha RA, Bruinstroop E, Singh BK, Yen PM. Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists. Thyroid. 2019;29:1173–91.
    1. Ali MA, Lacin S, Abdel-Wahab R, Uemura M, Hassan M, et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway? Onco Targets Ther. 2017;10:1403–12.
    1. Wu EM, Wong LL, Hernandez BY, Ji JF, Jia W, et al. Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation. Hepatoma Res. 2018;4
    1. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–16.
    1. Gan L, Chitturi S, Farrell GC. Mechanisms and implications of age-related changes in the liver: nonalcoholic fatty liver disease in the elderly. Curr Gerontol Geriatr Res. 2011;2011 831536.
    1. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46(Suppl 1):63–9.
    1. Iyer JK, Kalra M, Kaul A, Payton ME, Kaul R. Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis. World J Gastroenterol. 2017;23:6802–16.
    1. Kettner NM, Voicu H, Finegold MJ, Coarfa C, Sreekumar A, et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell. 2016;30:909–24.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren