1. 角田圭雄. NAFLD/NASH 診療戦略 2020 ~ガイドラインからパイプラインまで~ 明日の臨床, 2020, 31(1), 1-12.
2. Ministry of Health, Labour and Welfare: National Health and Nutrition Survey (2012)
3. Ascha, M. S.; Hanouneh, I. A.; Lopez, R., The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010, 51 (6), 1972-8.
4. Tokushige, K.; Hashimoto, E.; Yatsuji, S., Prospective study of hepatocellular carcinoma in nonalcoholic steatohepatitis in comparison with hepatocellular carcinoma caused by chronic hepatitis C. Journal of gastroenterology 2010, 45 (9), 960-967.)
5. Kawamura, Y.; Arase, Y.; Ikeda, K., 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 2012, 107 (2), 253-61.
6. Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non- alcoholic steatohepatitis: current knowledge and implications for management. World J Hepatol 2017; 9: 533-543.
7. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 2012; 56: 1384-1391.
8. Murata S, Ohkohchi N, Matsuo R, Ikeda O, Myronovych A, Hoshi R. Platelets promote liver regeneration in early period after hepatectomy in mice. World J Surg. 2007 Apr;31(4):808- 16.
9. Hisakura K, Murata S, Takahashi K, Matsuo R, Pak S, Ikeda N, Kawasaki T, Kohno K, Myronovych A, Nakano Y, Ikeda O, Watanabe M, Ohkohchi N. Platelets prevent acute hepatitis induced by anti-fas antibody. J Gastroenterol Hepatol. 2011 Feb;26(2):348-55.
10. Watanabe M, Murata S, Hashimoto I, Nakano Y, Ikeda O, Aoyagi Y, Matsuo R, Fukunaga K, Yasue H, Ohkohchi N. Platelets contribute to the reduction of liver fibrosis in mice. J Gastroenterol Hepatol. 2009 Jan;24(1):78-89.
11. Day CP, James OF. Steatohepatitis : a tale of two “hits”? Gastroenterology 1998; 114: 842- 845.
12. Tilg H Evolution of inflammation in nonalcoholic steatohepatitis: the multiple parallel hits hypothesis. Hepatology 52:1836-1846,2010
13. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Luts WDW. Crit Rev Toxicol. 2003;33:105-36.
14. Kirchgessner TG, Sleph P, Ostrowski J, et al. Beneficial and adverse effects of an LXR agonist on human lipid and lipoprotein metabolism and circulating neutrophils. Cell Metab 2016; 24: 223-233.
15. Owada Y, Tamura T, Tanoi T, et al. Novel non-alcoholic steatohepatitis model with histopathological and insulin-resistant features. Pathol Int 2018; 68: 12-22.
16. Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol- activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012 Mar 14;13(4):213-24.
17. illy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes & development. 1995;9:1033-45.
18. Silvente-Poirot S, Poirot M. Cholesterol epoxide hydrolase and cancer. Current opinion in pharmacology. 2012;12:696-703.
19. Edidin M. The state of lipid rafts: from model membranes to cells. Annual review of biophysics and biomolecular structure. 2003;32:257-83.
20. Zhuang L, Lin J, Lu ML, Solomon KR, Freeman MR. Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer research. 2002;62:2227-31.
21. Edwards PA, Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annual review of biochemistry. 1999;68:157-85.
22. 脂質代謝調節の分子機構 佐藤隆一郎. 化学と生物 42.5.2004. 300-308
23. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N ( 2008 ) HDL, ABC transporters, and choles- terol efflux: implications for the treatment of athero- sclerosis. Cell Metab 7: 365-375
24. Parikh M, Patel K, Soni S, Gandhi T. Liver X receptor: a cardinal target for atherosclerosis and beyond. Journal of atherosclerosis and thrombosis. 2014;21:519-31.
25. Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: potential new players in atherosclerosis. Nature medicine. 2002;8:1243-8.
26. Yasuda T, Grillot D, Billheimer JT, Briand F, Delerive P, Huet S, et al. Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo. Arteriosclerosis, thrombosis, and vascular biology. 2010;30:781-6.
27. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:7604-9.
28. Peng D, Hiipakka RA, Xie JT, Dai Q, Kokontis JM, Reardon CA, et al. A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR(-/-) mice. British journal of pharmacology. 2011;162:1792- 804.
29. Schultz J R, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis[J]. Genes & development, 2000, 14(22): 2831-2838.
30. Kumar N, Solt L A, Conkright J J, et al. The benzenesulfoamide T0901317 [N-(2, 2, 2- trifluoroethyl)-N-[4-[2, 2, 2-trifluoro-1-hydroxy-1-(trifluoromethyl) ethyl] phenyl]- benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-α/γ inverse agonist[J]. Molecular pharmacology, 2010, 77(2): 228-236.
31. Mitro N, Vargas L, Romeo R, et al. T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR. FEBS Lett. 2007 May 1;581(9):1721-6.
32. Willson TM, Kliewer SA. PXR, CAR and drug metabolism. Nat Rev Drug Discov. 2002; 1:259– 266.
33. Tolson AH, Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev. 2010; 62:1238–1249.
34. Griffiths WJ, Wang Y. Oxysterols as lipid mediators: Their biosynthetic genes, enzymes and metabolites. Prostaglandins Other Lipid Mediat. 2020 Apr;147:106381.
35. Janowski BA, Willy PJ, Devi TR, et al. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996 Oct 24;383(6602):728-31.
36. Cayman Chemical Co., Product Information of T0901317.
37. Ahn SB, Jang K, Jun DW, Lee BH, Shin KJ. Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Dig Dis Sci 2014; 59: 2975-2982.
38. Pekow JR, Bhan AK, Zheng H, Chung RT. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer 2007; 109: 2490-2496.
39. Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009; 8: 33-40.
40. Wang SN, Yang SF, Tsai HH, Lee KT, Yeh YT. Increased adiponectin associated with poor survival in hepatocellular carcinoma. J Gastroenterol 2014; 49: 1342-1351.
41. Chen MJ, Yeh YT, Lee KT, Tsai CJ, Lee HH, Wang SN. The promoting effect of adiponectin in hepatocellular carcinoma. J Surg Oncol 2012; 106: 181-187.
42. Rasband WS. ImageJ. Bethesda, Maryland: National Institutes of Health, 1997-2015.
43. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.
44. Ogawa Y, Imajo K, Yoneda M, et al. Soluble CD14 levels reflect liver inflammation in patients with nonalcoholic steatohepatitis. PLoS One. 2013 Jun 7;8(6):e65211.
45. Iguchi E, Takai A, Takeda H, et al. DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis. Sci Rep 10, 21268 (2020).
46. Zhou SG, Wang P, Pi RB, et al. Reduced expression of GSTM2 and increased oxidative stress in spontaneously hypertensive rat. Mol Cell Biochem 309, 99–107 (2008).
47. Xu G, Han X, Yuan G, et al. Screening for the protective effect target of deproteinized extract of calf blood and its mechanisms in mice with CCl4-induced acute liver injury. PLoS One. 2017 Jul 10;12(7)
48. Tillander V, Alexson SEH, Cohen DE. Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism. Trends Endocrinol Metab. 2017 Jul;28(7):473-484.
49. Teratani T, Tomita K, Furuhashi H, et al. Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice. Hepatol Commun. 2019 Jun 6;3(8):1098-1112.
50. Zhang XW, Zhou JC, Peng D, et al. Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation. Autophagy. 2020 May;16(5):782-796.
51. Medici V, Ali MR, Seo S et al. Increased soluble leptin receptor levels in morbidly obese patients with insulin resis- tance and nonalcoholic fatty liver disease. Obesity 2010; 18: 2268–73.
52. Pejnovic N, Jeftic I, Jovicic N, et al. Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis. World J Gastroenterol. 2016 Nov 28;22(44):9706-9717.
53. Takeo M, Kobayashi Y, Fujita N, et al. Upregulation of transferrin receptor 2 and ferroportin 1 mRNA in the liver of patients with chronic hepatitis C. J Gastroenterol Hepatol. 2005 Apr;20(4):562-9.
54. Mancardi DA, Iannascoli B, Hoos S, et al. FcgammaRIV is a mouse IgE receptor that resembles macrophage FcepsilonRI in humans and promotes IgE-induced lung inflammation. J Clin Invest. 2008 Nov;118(11):3738-50.
55. Aran G, Sanjurjo L, Bárcena C, et al. CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78). FASEB J. 2018 Jul;32(7):3878-3891.
56. Udali S, Guarini P, Ruzzenente A, et al. DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma. Clin Epigenet 7, 43 (2015).
57. Zhang B, Qin L, Zhou CJ, et al. SIRT3 expression in hepatocellular carcinoma and its impact on proliferation and invasion of hepatoma cells. Asian Pac J Trop Med. 2013 Aug;6(8):649-52.
58. Jiang Y, Zhang H, Dong LY, et al. Increased hepatic UCP2 expression in rats with nonalcoholic steatohepatitis is associated with upregulation of Sp1 binding to its motif within the proximal promoter region. J Cell Biochem. 2008 Sep 1;105(1):277-89.
59. Park SS, Eom YW, Kim EH, et al. Involvement of c-Src kinase in the regulation of TGF- beta1-induced apoptosis. Oncogene. 2004 Aug 19;23(37):6272-81.
60. Kim HS, Han HD, Armaiz-Pena GN, et al. Functional roles of Src and Fgr in ovarian carcinoma. Clin Cancer Res. 2011 Apr 1;17(7):1713-21.
61. Cipriano R, Miskimen KL, Bryson BL, Foy CR, Bartel CA, Jackson MW. Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer. Mol Cancer Res. 2014;12(8):1156-1165. doi:10.1158/1541-7786.MCR-13-0289
62. Walker S, Wankell M, Ho V, et al. Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel murine liver cancer model. PLoS One. 2019 Feb 22;14(2)
63. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta- analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13: 643-654.e641-649; quiz e639-640.
64. Cave MC, Clair HB, Hardesty JE, et al. Nuclear receptors and nonalcoholic fatty liver disease. Biochim Biophys Acta 2016; 1859: 1083-1099.
65. Zhou J, Febbraio M, Wada T, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008; 134: 556-567.
66. Xiong T, Li Z, Huang X, et al. TO901317 inhibits the development of hepatocellular carcinoma by LXRalpha/Glut1 decreasing glycometabolism. Am J Physiol Gastrointest Liver Physiol 2019; 316: G598-G607.
67. Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20: 15539-15548.
68. Nada P, Llija J, Nemanja J, et al. Galectin-3 and IL-33/ST2 axis roles and interplay in diet- induced steatohepatitis. World J Gastroenterol 2016; 22: 9706-9717.
69. Liu W, Baker RD, Bhatia T, Zhu L, Baker SS. Pathogenesis of nonalcoholic steatohepatitis. Cell Mol Life Sci 2016; 73: 1969-1987.
70. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37: 917-923.
71. McClain CJ, Barve S, Deaciuc I. Good fat/bad fat. Hepatology 2007; 45: 1343-1346.
72. Itoh M, Suganami T, Nakagawa N, et al. Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am J Pathol 2011; 179: 2454-2463.
73. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784-1792.
74. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183- 1192.
75. Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76: 99-128.
76. Muscat GE, Wagner BL, Hou J, et al. Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors. J Biol Chem 2002; 277: 40722-40728.
77. Lee J, Kim MS. The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res Clin Pract 2007; 77: S49-S57.
78. Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol 2012; 56: 704-713.
79. Wang F, Jing X, Wang T, et al. Differential diagnostic value of GPC3-CD34 combined staining in small liver nodules with diameter less than 3 cm. Am J Clin Pathol 2012; 137: 937-945.
80. Tsuboi Y, Ichida T, Sugitani S, et al. Overexpression of extracellular signal-regulated protein kinase and its correlation with proliferation in human hepatocellular carcinoma. Liver Int 2004; 24: 432-436.
81. Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000; 351 Pt 2: 289-305.
82. Patil MA, Lee SA, Macias E, et al. Role of cyclin D1 as a mediator of c-Met- and beta- catenin-induced hepatocarcinogenesis. Cancer Res 2009; 69: 253-261.
83. Gutierrez-Uzquiza A, Arechederra M, Bragado P, Aguirre-Ghiso JA, Porras A. p38alpha mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathway. J Biol Chem 2012; 287: 2632-2642.
84. Igea A, Nebreda AR. The stress kinase p38alpha as a target for cancer therapy. Cancer Res 2015; 75: 3997-4002.
85. Cipriano R, Miskimen KL, Bryson BL, Foy CR, Bartel CA, Jackson MW. Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer. Mol Cancer Res 2014; 12: 1156-1165.
86. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001; 98: 7522-7527.
87. Wheeler DL, Iida M, Dunn EF. The role of Src in solid tumors. Oncologist 2009; 14: 667- 678.
88. Lin CY, Gustafsson JA. Targeting liver X receptors in cancer therapeutics. Nat Rev Cancer 2015; 15: 216-224.
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