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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases

Published online by Cambridge University Press:  01 February 2019

Sabrina Campisano
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
Anabela La Colla
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
Stella M. Echarte
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
Andrea N. Chisari
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
E-mail address:


Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of ‘developmental origins of health and disease’. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.

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© The Authors 2019 

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1. Barker, DJ (2004) The developmental origins of chronic adult disease. Acta Paediatr 93, 2633.CrossRefGoogle ScholarPubMed
2. Brumbaugh, DE & Friedman, JE (2014) Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 75, 140147.CrossRefGoogle ScholarPubMed
3. Gallego-Durán, R & Romero-Gómez, M (2015) Epigenetic mechanisms in non-alcoholic fatty liver disease: an emerging field. World J Hepatol 7, 24972502.CrossRefGoogle Scholar
4. Paparo, L, di Costanzo, M, di Scala, C, et al. (2014) The influence of early life nutrition on epigenetic regulatory mechanisms of the immune system. Nutrients 6, 47064719.CrossRefGoogle ScholarPubMed
5. Singer, C, Stancu, P, Coşoveanu, S, et al. (2014) Non-alcoholic fatty liver disease in children. Curr Health Sci J 40, 170176.Google ScholarPubMed
6. Black, RE, Victora, CG, Walker, SP, et al. (2013) Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382, 427451.CrossRefGoogle ScholarPubMed
7. Victora, CG, Adair, L, Fall, C, et al. (2008) Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371, 340357.CrossRefGoogle ScholarPubMed
8. Hales, CN & Barker, DJP (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595601.CrossRefGoogle ScholarPubMed
9. Gluckman, PD & Hanson, MA (2004) The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15, 183187.CrossRefGoogle ScholarPubMed
10. Barker, DJ, Eriksson, JG & Forsén, T (2002) Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 31, 12351239.CrossRefGoogle ScholarPubMed
11. Ravelli, ACJ, van Der Meulen, JH, Osmond, C, et al. (1999) Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70, 811816.CrossRefGoogle Scholar
12. Roseboom, T, de Rooij, S & Painter, R (2006) The Dutch famine and its long-term consequences for adult health. Early Hum Dev 82, 485491.CrossRefGoogle ScholarPubMed
13. Ross, MG & Beall, MH (2008) Adult sequelae of intrauterine growth restriction. Semin Perinatol 32, 213218.CrossRefGoogle ScholarPubMed
14. Pettitt, DJ, Baird, HR, Aleck, KA, et al. (1983) Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N Eng J Med 308, 242245.CrossRefGoogle ScholarPubMed
15. Shankar, K, Harrell, A, Liu, X, et al. (2008) Maternal obesity at conception programs obesity in the offspring. Am J Physiol Regul Integr Comp Physiol 294, R528R538.CrossRefGoogle ScholarPubMed
16. Boney, CM, Verma, A, Tucker, R, et al. (2005) Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 115, e290e296.CrossRefGoogle ScholarPubMed
17. Whitaker, RC (2004) Predicting preschooler obesity at birth: the role of maternal obesity in early pregnancy. Pediatrics 114, e29e36.CrossRefGoogle ScholarPubMed
18. Pardee, PE, Lavine, E & Schwimmer, JB (2009) Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery. Semin Pediatr Surg 18, 144151.CrossRefGoogle ScholarPubMed
19. Correia-Branco, A, Keating, E & Martel, F (2015) Maternal undernutrition and fetal developmental programming of obesity: the glucocorticoid connection. Reprod Sci 22, 138145.CrossRefGoogle ScholarPubMed
20. Wang, N, Chen, Y, Ning, Z, et al. (2016) Exposure to famine in early life and nonalcoholic fatty liver disease in adulthood. J Clin Endocrinol Metab 101, 22182225.CrossRefGoogle ScholarPubMed
21. Fraser, A, Ebrahim, S, Smith, GD, et al. (2008) The associations between birthweight and adult markers of liver damage and function. Paediatr Perinat Epidemiol 22, 1221.Google ScholarPubMed
22. Wang, N, Wang, X, Han, B, et al. (2015) Is exposure to famine in childhood and economic development in adulthood associated with diabetes? J Clin Endocrinol Metab 100, 45144523.CrossRefGoogle ScholarPubMed
23. Wang, N, Wang, X, Li, Q, et al. (2017) The famine exposure in early life and metabolic syndrome in adulthood. Clin Nutr 36, 253259.CrossRefGoogle ScholarPubMed
24. Cianfarani, S, Agostoni, C, Bedogni, G, et al. (2012) Effect of intrauterine growth retardation on liver and long-term metabolic risk. Int J Obes 36, 12701277.CrossRefGoogle ScholarPubMed
25. Dietrich, P & Hellerbrand, C (2014) Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol 28, 637653.CrossRefGoogle ScholarPubMed
26. Byrne, CD & Targher, GJ (2015) NAFLD: a multisystem disease. J Hepatol 62, Suppl. 1, S47S64.CrossRefGoogle ScholarPubMed
27. Ekstedt, M, Franzén, LE, Mathiesen, UL, et al. (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865873.CrossRefGoogle ScholarPubMed
28. Farazi, PA & De Pinho, RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6, 674687.CrossRefGoogle Scholar
29. Wu, SD, Ma, YS, Fang, Y, et al. (2012) Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev 38, 218225.CrossRefGoogle ScholarPubMed
30. Younossi, ZM, Gramlich, T, Matteoni, CA, et al. (2004) Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2, 262265.CrossRefGoogle ScholarPubMed
31. Park, EJ, Lee, JH, Yu, GY, et al. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197208.CrossRefGoogle ScholarPubMed
32. Stickel, F & Hellerbrand, C (2010) Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut 59, 13031307.CrossRefGoogle ScholarPubMed
33. Mirza, MS (2011) Obesity, visceral fat, and NAFLD: querying the role of adipokines in the progression of nonalcoholic fatty liver disease. ISRN Gastroenterol 2011, 592404.CrossRefGoogle ScholarPubMed
34. Vinciguerra, M, Carrozzino, F, Peyrou, M, et al. (2009) Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. J Hepatol 50, 11321141.CrossRefGoogle ScholarPubMed
35. Wei, Y, Wang, D, Topczewski, F, et al. (2006) Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291, E275E281.CrossRefGoogle ScholarPubMed
36. Malhi, H, Bronk, SF, Werneburg, NW, et al. (2006) Free fatty acids induce JNK dependent hepatocyte lipoapoptosis. J Biol Chem 281, 1209312101.CrossRefGoogle ScholarPubMed
37. Gallagher, EJ & Le Roith, D (2011) Mini review: IGF, insulin, and cancer. Endocrinology 152, 25462551.CrossRefGoogle Scholar
38. Jang, H & Serra, C (2014) Nutrition, epigenetics, and diseases. Clin Nutr Res 3, 18.CrossRefGoogle ScholarPubMed
39. Lee, JH, Friso, S & Choi, SW (2014) Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients 6, 33033325.CrossRefGoogle ScholarPubMed
40. Franco, R, Schoneveld, O, Georgakilas, AG, et al. (2008) Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett 266, 611.CrossRefGoogle ScholarPubMed
41. Lahtz, C & Pfeifer, GP (2011) Epigenetic changes of DNA repair genes in cancer. J Mol Cell Biol 3, 5158.CrossRefGoogle Scholar
42. Niculescu, MD & Zeisel, SH (2002) Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 132, Suppl. 8, 2333S2335S.CrossRefGoogle ScholarPubMed
43. Anderson, OS, Sant, KE & Dolinoy, DC (2012) Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism, and DNA methylation. J Nutr Biochem 23, 853859.CrossRefGoogle ScholarPubMed
44. Lillycrop, KA, Phillips, ES, Torrens, C, et al. (2008) Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARα promoter of the offspring. Br J Nutr 100, 278282.CrossRefGoogle ScholarPubMed
45. Reamon-Buettner, SM, Buschmann, J & Lewin, G (2014) Identifying placental epigenetic alterations in an intrauterine growth restriction (IUGR) rat model induced by gestational protein deficiency. Reprod Toxicol 45, 117124.CrossRefGoogle Scholar
46. Gong, L, Pan, YX & Chen, H (2010) Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics 5, 619626.CrossRefGoogle ScholarPubMed
47. Dudley, KJ, Sloboda, DM, Connor, KL, et al. (2011) Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation. PLoS ONE 6, e21662.CrossRefGoogle ScholarPubMed
48. Pruis, MGM, Lendvai, A, Bloks, VW, et al. (2014) Maternal Western diet primes non‐alcoholic fatty liver disease in adult mouse offspring. Acta Physiol 210, 215227.CrossRefGoogle ScholarPubMed
49. Varga, T, Czimmerer, Z & Nagy, L (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812, 10071022.CrossRefGoogle ScholarPubMed
50. Sun, C, Fan, JG, Qiao, L (2015) Potential epigenetic mechanism in non-alcoholic fatty liver disease. Int J Mol Sci 16, 51615179.CrossRefGoogle ScholarPubMed
51. Giby, VG & Ajith, TA (2014) Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol 6, 570579.CrossRefGoogle ScholarPubMed
52. Sookoian, S, Rosselli, MS, Gemma, C, et al. (2010) Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 52, 19922000.CrossRefGoogle ScholarPubMed
53. Chen, G, Broséus, J, Hergalant, S, et al. (2015) Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: relevance to nonalcoholic liver disease. Mol Nutr Food Res 59, 293302.CrossRefGoogle ScholarPubMed
54. Pirola, CJ, Gianotti, TF, Burgueño, AL, et al. (2013) Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62, 13561363.CrossRefGoogle ScholarPubMed
55. Murphy, SK, Yang, H, Moylan, CA, et al. (2013) Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 145, 10761087.CrossRefGoogle ScholarPubMed
56. Ahrens, M, Ammerpohl, O, von Schönfels, W, et al. (2013) DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab 18, 296302.CrossRefGoogle ScholarPubMed
57. Heijmans, BT, Tobi, EW, Stein, AD, et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105, 1704617049.CrossRefGoogle ScholarPubMed
58. Ling, C & Groop, L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58, 27182725.CrossRefGoogle ScholarPubMed
59. Tian, Y, Wong, VW, Chan, HL, et al. (2013) Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin Cancer Biol 23, 471482.CrossRefGoogle ScholarPubMed
60. Feige, J & Auwerx, J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20, 303309.CrossRefGoogle ScholarPubMed
61. Purushotham, A, Schug, TT, Xu, Q, et al. (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9, 327338.CrossRefGoogle ScholarPubMed
62. Hirschey, MD, Shimazu, T, Jing, E, et al. (2011) SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44, 177190.CrossRefGoogle ScholarPubMed
63. Aagaard-Tillery, KM, Grove, K, Bishop, J, et al. (2008) Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 41, 91102.CrossRefGoogle ScholarPubMed
64. Bricambert, J, Miranda, J, Benhamed, F, et al. (2010) Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest 120, 43164331.CrossRefGoogle ScholarPubMed
65. Feng, D, Liu, T, Sun, Z, et al. (2011) A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 13151319.CrossRefGoogle ScholarPubMed
66. Mazzoccoli, G, Vinciguerra, M, Oben, J, et al. (2014) Non-alcoholic fatty liver disease: the role of nuclear receptors and circadian rhythmicity. Liver Int 34, 11331152.CrossRefGoogle ScholarPubMed
67. Gueant, JL, Namour, F, Gueant-Rodriguez, RM, et al. (2013) Folate and fetal programming: a play in epigenomics? Trends Endocrinol Metab 24, 279289.CrossRefGoogle ScholarPubMed
68. Portha, B, Fournier, A, Kioon, MD, et al. (2014) Early environmental factors, alteration of epigenetic marks and metabolic disease susceptibility. Biochimie 97, 115.CrossRefGoogle ScholarPubMed
69. Lynn, FC (2009) Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol Metab 20, 452459.CrossRefGoogle ScholarPubMed
70. Lakner, AM, Bonkovsky, HL & Schrum, LW (2011) microRNAs: fad or future of liver disease. World J Gastroenterol 17, 25362542.CrossRefGoogle ScholarPubMed
71. Cheung, O, Puri, P, Eicken, C, et al. (2008) Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48, 18101820.CrossRefGoogle ScholarPubMed
72. Zhang, J, Zhang, F, Didelot, X, et al. (2009) BMC maternal high fat diet during pregnancy and lactation alters hepatic expression of insulin like growth factor-2 and key microRNAs in the adult offspring. Genomics 10, 478.Google ScholarPubMed
73. Tessitore, A, Cicciarelli, G, Del Vecchio, F, et al. (2016) MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice. BMC Cancer 16, 3.CrossRefGoogle Scholar
74. Hsu, SH, Wang, B, Kota, J, et al. (2012) Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 122, 28712883.CrossRefGoogle ScholarPubMed
75. Wen, J & Friedman, JR (2012) miR-122 regulates hepatic lipid metabolism and tumor suppression. J Clin Invest 122, 27732776.CrossRefGoogle ScholarPubMed
76. Seki, E & Brenner, DA (2008) Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48, 322335.CrossRefGoogle ScholarPubMed
77. Machado, M, Marques-Vidal, P & Cortez-Pinto, H (2006) Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 45, 600606.CrossRefGoogle ScholarPubMed
78. Gregor, MF & Hotamisligil, GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29, 415445.CrossRefGoogle ScholarPubMed
79. Bartz, S, Mody, A, Hornik, C, et al. (2014) Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality. J Clin Endocrinol Metab 99, 21282137.CrossRefGoogle ScholarPubMed
80. Robinson, MW, Harmon, C & O’Farrelly, C (2016) Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 13, 267276.CrossRefGoogle ScholarPubMed
81. Smedsrod, B, De Bleser, PJ, Braet, F, et al. (1994) Cell biology of liver endothelial and Kupffer cells. Gut 35, 15091516.CrossRefGoogle ScholarPubMed
82. Bilzer, M, Roggel, F & Gerbes, AL (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26, 11751186.CrossRefGoogle ScholarPubMed
83. Su, GL, Klein, RD, Aminlari, A, et al. (2000) Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and toll-like receptor 4. Hepatology 31, 932936.CrossRefGoogle ScholarPubMed
84. Schieferdecker, HL, Schlaf, G, Jungermann, K, et al. (2001) Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells. Int Immunopharmacol 1, 469481.CrossRefGoogle ScholarPubMed
85. van Egmond, M, van Garderen, E, van Spriel, AB, et al. (2000) FcαRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 6, 680685.CrossRefGoogle ScholarPubMed
86. Wu, J, Meng, Z, Jiang, M, et al. (2010) Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology 129, 363374.CrossRefGoogle ScholarPubMed
87. Miura, K, Yang, L, van Rooijen, N, et al. (2013) Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57, 577589.CrossRefGoogle ScholarPubMed
88. Sica, A & Mantovani, A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122, 787795.CrossRefGoogle ScholarPubMed
89. Biswas, SK & Mantovani, A (2012) Orchestration of metabolism by macrophages. Cell Metab 15, 432437.CrossRefGoogle ScholarPubMed
90. Paz, K, Hemi, R, Le Roith, D, et al. (1997) A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxta membrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 272, 2991129918.CrossRefGoogle Scholar
91. Abiru, S, Migita, K, Maeda, Y, et al. (2006) Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int 26, 3945.CrossRefGoogle ScholarPubMed
92. Haukeland, JW, Damas, JK, Konopski, Z, et al. (2006) Systemic inflammation in non-alcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 44, 11671174.CrossRefGoogle Scholar
93. Bonizzi, G & Karin, M (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25, 280288.CrossRefGoogle ScholarPubMed
94. Lawrence, T & Gilroy, DW (2007) Chronic inflammation: a failure of resolution? Int J Exp Pathol 88, 8594.CrossRefGoogle ScholarPubMed
95. Hagemann, T, Lawrence, T, McNeish, I, et al. (2008) “Re-educating” tumor-associated macrophages by targeting NF-κB. J Exp Med 205, 12611268.CrossRefGoogle ScholarPubMed
96. Gatselis, NK, Ntaios, G, Makaritsis, K, et al. (2013) Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease. Clin Exp Med 14, 121131.CrossRefGoogle ScholarPubMed
97. Takeda, N, O’Dea, EL, Doedens, A, et al. (2010) Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev 24, 491501.CrossRefGoogle ScholarPubMed
98. Han, MS, Jung, DY, Morel, C, et al. (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339, 218222.CrossRefGoogle ScholarPubMed
99. Liu, Y, Chen, K, Wang, C, et al. (2013) Cell surface receptor FPR2 promotes antitumor host defense by limiting m2 polarization of macrophages. Cancer Res 73, 550560.CrossRefGoogle ScholarPubMed
100. Wan, J, Benkdane, M, Teixeira-Clerc, F, et al. (2014) M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59, 130142.CrossRefGoogle ScholarPubMed
101. Ekihiro, S & Brenner, DA (2008) Toll-like receptors and adaptor molecules in liver disease: updates. Hepatology 48, 322335.Google Scholar
102. Aoyama, T, Paik, YH & Seki, E (2010) Toll-like receptor signalling and liver fibrosis. Gastroenterol Res Pract 2010, 192543.CrossRefGoogle Scholar
103. Iimuro, Y & Fujimoto, J (2010) TLRs, NF-κB, JNK, and liver regeneration. Gastroenterol Res Pract 2010, 598109.CrossRefGoogle ScholarPubMed
104. Miura, K, Kodama, Y, Inokuchi, S, et al. (2010) Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139, 323334.CrossRefGoogle ScholarPubMed
105. Rivera, CA, Gaskin, L, Allman, M, et al. (2010) Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis. BMC Gastroenterol 10, 52.CrossRefGoogle ScholarPubMed
106. Csak, T, Velayudham, A, Hritz, I, et al. (2011) Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates non-alcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 300, 433441.CrossRefGoogle ScholarPubMed
107. Spruss, A, Kanuri, G, Wagnerberger, S, et al. (2009) Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50, 10941104.CrossRefGoogle ScholarPubMed
108. Martinon, F, Mayor, A & Tschopp, J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27, 229265.CrossRefGoogle Scholar
109. Pedra, JH, Cassel, SL & Sutterwala, FS (2009) Sensing pathogens and danger signals by the inflammasome. Curr Opin Immunol 21, 1016.CrossRefGoogle ScholarPubMed
110. Dixon, LJ, Flask, CA, Papouchado, BG, et al. (2013) Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLOS ONE 8, e56100.CrossRefGoogle ScholarPubMed
111. Csak, T, Ganz, M, Pespisa, J, et al. (2011) Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 54, 133144.CrossRefGoogle ScholarPubMed
112. Eun-Kyeong, J, Jin Kyung, K, Dong-Min, S, et al. (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 13, 148159.Google Scholar
113. Doherty, DG (2016) Antigen-presenting cell function in the tolerogenic liver environment. J Autoimmun 66, 6075.CrossRefGoogle Scholar
114. Rahman, AH & Aloman, C (2013) Dendritic cells and liver fibrosis. Biochim Biophys Acta 1832, 9981004.CrossRefGoogle ScholarPubMed
115. Eckert, C, Klein, N, Kormek, M, et al. (2016) The complex myeloid network of the liver with diverse functional capacity at steady state and in inflammation. Front Immunol 6, 179.Google Scholar
116. Heymann, F & Take, F (2016) Immunology of the liver – from homeostasis to disease. Nat Rev Gastroenteol Hepatol 13, 88110.CrossRefGoogle ScholarPubMed
117. Thomson, AW & Knolle, PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10, 753766.CrossRefGoogle ScholarPubMed
118. Ibrahim, J, Nguyen, AH, Rehman, A, et al. (2012) Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver. Gastroenterology 143, 10611072.CrossRefGoogle ScholarPubMed
119. Henning, JR, Graffeo, CS, Rehman, A, et al. (2013) Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58, 589602.CrossRefGoogle ScholarPubMed
120. Sutti, S, Jindal, A, Locatelli, I, et al. (2014) Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59, 886897.CrossRefGoogle ScholarPubMed
121. Wolf, MJ, Adili, A, Piotrowitz, K, et al. (2014) Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549564.CrossRefGoogle ScholarPubMed
122. Heier, E-C, Meier, A, Julich-Haertel, H, et al. (2017) Murine CD103+ dendritic cells protect against steatosis progression towards steatohepatitis. J Hepatol 66, 12411250.CrossRefGoogle ScholarPubMed
123. Bernsmeier, C & Albano, E (2017) Liver dendritic cells and NAFLD evolution: a remaining open issue. J Hepatol 66, 11201122.CrossRefGoogle ScholarPubMed
124. Dutertre, CA, Wang, LF & Ginhoux, F (2014) Aligning bona fide dendritic cell populations across species. Cell Immunol 291, 310.CrossRefGoogle ScholarPubMed
125. Kelly, A, Fahey, R, Fletcher, JM, et al. (2014) CD141+ myeloid dendritic cells are enriched in healthy human liver. J Hepatol 60, 135142.CrossRefGoogle ScholarPubMed
126. Gabrilovich, DI & Nagaraj, S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9, 162174.CrossRefGoogle ScholarPubMed
127. Höchst, B, Schildberg, FA, Sauerborn, P, et al. (2013) Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J Hepatol 59, 528535.CrossRefGoogle Scholar
128. Chou, HS, Hsieh, CC, Yang, HR, et al. (2011) Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 53, 10071019.CrossRefGoogle ScholarPubMed
129. Hsieh, CC, Chou, HS, Yang, HR, et al. (2013) The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 121, 17601768.CrossRefGoogle ScholarPubMed
130. Yen, BL, Yen, ML, Hsu, PJ, et al. (2013) Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3. Stem Cell Reports 1, 139151.CrossRefGoogle ScholarPubMed
131. Chen, S, Akbar, SMF, Abe, M, et al. (2011) Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol 166, 134142.CrossRefGoogle Scholar
132. Pallett, LJ, Gill, US, Quaglia, A, et al. (2015) Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med 21, 591600.CrossRefGoogle ScholarPubMed
133. Schneider, C, Teufel, A, Yevsa, T, et al. (2012) Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61, 17331743.CrossRefGoogle ScholarPubMed
134. Hammerich, L & Tacke, F (2015) Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis. World J Gastrointest Pathophysiol 6, 4350.CrossRefGoogle ScholarPubMed
135. Yao, L, Abe, M, Kawasaki, K, et al. (2016) Characterization of liver monocytic myeloid-derived suppressor cells and their role in a murine model of non-alcoholic fatty liver disease. PLOS ONE 11, e0149948.CrossRefGoogle Scholar
136. Huang, B, Lei, Z, Zhao, J, et al. (2007) CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett 252, 8692.CrossRefGoogle ScholarPubMed
137. Boelte, KC, Gordy, LE, Joyce, S, et al. (2011) Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1. PLoS ONE 6, e18534.CrossRefGoogle ScholarPubMed
138. Hale, M, Itani, F, Buchta, CM, et al. (2015) Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2. PLOS ONE 10, e0118784.CrossRefGoogle ScholarPubMed
139. Ganz, M & Szabo, G (2013) Immune and inflammatory pathways in NASH. Hepatol Int 7, 771781.CrossRefGoogle ScholarPubMed
140. Tian, Z, Chen, Y & Gao, B (2013) Natural killer cells in liver disease. Hepatology 57, 16541662.CrossRefGoogle ScholarPubMed
141. Bhattacharjee Kumar, J, Arindkar, JMS, Das, B, et al. (2014) Role of immunodeficient animal models in the development of fructose induced NAFLD. J Nutr Biochem 25, 219226.CrossRefGoogle Scholar
142. Krizhanovsky, V, Yon, M, Dickins, RA, et al. (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657667.CrossRefGoogle ScholarPubMed
143. Radaeva, S, Wang, L, Radaev, S, et al. (2007) Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1. Am J Physiol Gastrointest Liver Physiol 293, G809G816.CrossRefGoogle ScholarPubMed
144. Wehr, A, Baeck, C, Heymann, F, et al. (2013) Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J Immunol 190, 52265236.CrossRefGoogle ScholarPubMed
145. Syn, WK, Agboola, KM, Swiderska, M, et al. (2012) NKT associated Hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 13231329.CrossRefGoogle ScholarPubMed
146. Norris, S, Collins, C, Doherty, DG, et al. (1998) Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 28, 8490.CrossRefGoogle ScholarPubMed
147. Pruvot, FR, Navarro, F, Janin, A, et al. (1995) Characterization, quantification, and localization of passenger T lymphocytes and NK cells in human liver before transplantation. Transpl Int 8, 273279.CrossRefGoogle ScholarPubMed
148. Romagnani, S (1992) Type 1 T helper and type 2 T helper cells: functions, regulation and role in protection and disease. Int J Clin Lab Res 21, 152158.CrossRefGoogle Scholar
149. Tang, Y, Bian, Z, Zhao, L, et al. (2011) Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol 166, 281290.CrossRefGoogle ScholarPubMed
150. Sell, H, Habich, C & Eckel, J (2012) Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 8, 709716.CrossRefGoogle ScholarPubMed
151. Brunt, EM (2010) Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7, 195203.CrossRefGoogle ScholarPubMed
152. Inzaugarat, ME, Ferreyra Solari, NE, Billordo, LA, et al. (2011) Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol 31, 11201130.CrossRefGoogle ScholarPubMed
153. Boujedidi, H, Robert, O, Bignon, A, et al. (2015) CXCR4 dysfunction in nonalcoholic steatohepatitis in mice and patients. Clin Sci (Lond) 128, 257267.CrossRefGoogle Scholar
154. Tan, Z, Qian, X, Jiang, R, et al. (2013) IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol 191, 18351844.CrossRefGoogle Scholar
155. Meng, F, Wang, K, Aoyama, T, et al. (2012) Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765776.CrossRefGoogle ScholarPubMed
156. Rau, M, Schilling, AK, Meertens, J, et al. (2016) Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. J Immunol 196, 97105.CrossRefGoogle ScholarPubMed
157. Albano, E, Mottaran, E, Vidali, M, et al. (2005) Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut 54, 987993.CrossRefGoogle ScholarPubMed
158. Nobili, V, Parola, M, Alisi, A, et al. (2010) Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Int J Mol Med 26, 471476.CrossRefGoogle ScholarPubMed
159. Winer, DA, Winer, S, Shen, L, et al. (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17, 610617.CrossRefGoogle ScholarPubMed
160. Kawasaki, K, Abe, M, Tada, F, et al. (2013) Blockade of B-cell activating factor signaling enhances hepatic steatosis induced by a high-fat diet and improves insulin sensitivity. Lab Invest 93, 311321.CrossRefGoogle ScholarPubMed
161. Kim, DH & Do, MS (2015) BAFF knockout improves systemic inflammation via regulating adipose tissue distribution in high-fat diet-induced obesity. Exp Mol Med 47, e129.CrossRefGoogle ScholarPubMed
162. Weiskirchen, R & Tacke, F (2014) Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr 3, 344363.Google ScholarPubMed
163. Thapa, M, Chinnadurai, R, Velazquez, VM, et al. (2015) Liver fibrosis occurs through dysregulation of MyD88-dependent innate B cell activity. Hepatology 61, 20672079.CrossRefGoogle ScholarPubMed
164. Ramadori, G & Saile, B (2004) Portal tract fibrogenesis in the liver. Lab Invest 84, 153159.CrossRefGoogle ScholarPubMed
165. Kobold, D, Grundmann, A, Piscaglia, F, et al. (2002) Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts. J Hepatol 36, 607613.CrossRefGoogle ScholarPubMed
166. Dranoff, JA, Kruglov, EA, Robson, SC, et al. (2002) The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver. Hepatology 36, 11351144.CrossRefGoogle Scholar
167. Elpek, GO (2014) Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J Gastroenterol 20, 72607276.CrossRefGoogle ScholarPubMed
168. Guy, CD, Suzuki, A, Zdanowicz, M, et al. (2012) Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55, 17111721.CrossRefGoogle ScholarPubMed
169. Seki, E, De Minicis, S, Osterreicher, CH, et al. (2007) TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 13, 13241332.CrossRefGoogle ScholarPubMed
170. Liu, S, Gallo, DJ, Green, AM, et al. (2002) Role of toll-like receptors in changes in gene expression and NFκB activation in mouse hepatocytes stimulated with lipopolysaccharide. Infect Immun 70, 34333442.CrossRefGoogle Scholar
171. Matsumura, T, Degawa, T, Takii, T, et al. (2003) TRAF6-NF-κB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes. Immunology 109, 127136.CrossRefGoogle ScholarPubMed
172. Chiba, M, Sasaki, M, Kitamura, S, et al. (2011) Participation of bile ductular cells in the pathological progression of non-alcoholic fatty liver disease. J Clin Pathol 64, 564570.CrossRefGoogle ScholarPubMed
173. Harada, K, Ohira, S, Isse, K, et al. (2003) Lipopolysaccharide activates nuclear factor-κB through toll-like receptors and related molecules in cultured biliary epithelial cells. Lab Invest 83, 16571667.CrossRefGoogle ScholarPubMed
174. Lleo, A & Invernizzi, P (2013) Apotopes and innate immune system: novel players in the primary biliary cirrhosis scenario. Dig Liver Dis 45, 630636.CrossRefGoogle ScholarPubMed
175. Uhrig, A, Banafsche, R, Kremer, M, et al. (2005) Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J Leukoc Biol 77, 626633.CrossRefGoogle ScholarPubMed
176. Crispe, IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27, 147163.CrossRefGoogle ScholarPubMed
177. Barrès, R, Kirchner, H, Rasmussen, M, et al. (2013) Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep 3, 10201027.CrossRefGoogle ScholarPubMed
178. Donkin, I, Versteyhe, S, Ingerslev, LR, et al. (2016) Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab 23, 369378.CrossRefGoogle ScholarPubMed
179. Martínez, D, Pentinat, T, Ribó, S, et al. (2014) In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell Metab 19, 941951.CrossRefGoogle ScholarPubMed
180. Mann, J, Chu, DC, Maxwell, A, et al. (2010) MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705714.CrossRefGoogle ScholarPubMed
181. Zeybel, M, Hardy, T, Wong, YK, et al. (2012) Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med 18, 13691377.CrossRefGoogle ScholarPubMed
182. Younossi, ZM, Stepanova, M, Afendy, M, et al. (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9, 524530.e1.CrossRefGoogle ScholarPubMed
183. Wang, X, Zhu, H, Snieder, H, et al. (2010) Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Med 8, 87.CrossRefGoogle ScholarPubMed
184. Hermsdorff, HH, Mansego, ML, Campión, J, et al. (2013) TNF-α promoter methylation in peripheral white blood cells: relationship with circulating TNFα, truncal fat and n-6 PUFA intake in young women. Cytokine 64, 265271.CrossRefGoogle ScholarPubMed
185. Simar, D, Versteyhe, S, Donkin, I, et al. (2014) DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human. Metabolism 63, 11881197.CrossRefGoogle Scholar
186. Yang, X, Wang, X, Liu, D, et al. (2014) Epigenetic regulation of macrophage polarization by DNA methyl transferase 3b. Mol Endocrinol 28, 565574.CrossRefGoogle Scholar
187. Herath, NI, Leggett, BA & MacDonald, GA (2006) Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 21, 1521.CrossRefGoogle ScholarPubMed
188. Zhou, Y, Zhang, X & Klibanski, A (2014) Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma. Mol Cell Endocrinol 386, 1633.CrossRefGoogle ScholarPubMed
189. Amodio, N, Bellizzi, D, Leotta, M, et al. (2013) miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells. Cell Cycle 12, 36503662.CrossRefGoogle ScholarPubMed
190. Cheng, C, Huang, C, Ma, TT, et al. (2014) SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide induced inflammatory cytokines in macrophages. Toxicol Lett 225, 488497.CrossRefGoogle ScholarPubMed
191. Martinez-Chantar, ML, Vazquez-Chantada, M, Ariz, U, et al. (2008) Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology 47, 11911199.CrossRefGoogle ScholarPubMed
192. Schoenborn, JR, Dorschner, MO, Sekimata, M, et al. (2007) Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-γ. Nat Immunol 8, 732742.CrossRefGoogle ScholarPubMed
193. Di Spirito, JR & Shen, H (2010) Histone acetylation at the single-cell level: a marker of memory CD8+ T cell differentiation and functionality. J Immunol 184, 46314636.CrossRefGoogle Scholar
194. Abu-Farha, M, Tiss, A, Abubaker, J, et al. (2013) Proteomics analysis of human obesity reveals the epigenetic factor HDAC4 as a potential target for obesity. PLOS ONE 8, e75342.CrossRefGoogle ScholarPubMed
195. Miao, F, Gonzalo, IG, Lanting, L, et al. (2004) In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J Biol Chem 279, 1809118097.CrossRefGoogle ScholarPubMed
196. Li, Y, Reddy, MA, Miao, F, et al. (2008) Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-κB-dependent inflammatory genes: relevance to diabetes and inflammation. J Biol Chem 283, 2677126781.CrossRefGoogle ScholarPubMed
197. Tian, W, Xu, H, Fang, F, et al. (2013) Brahma-related gene 1 bridges epigenetic regulation of proinflammatory cytokine production to steatohepatitis in mice. Hepatology 58, 576588.CrossRefGoogle ScholarPubMed
198. Mikula, M, Majewska, A, Ledwon, JK, et al. (2014) Obesity increases histone H3 lysine 9 and 18 acetylation at TNFα and CCL2 genes in mouse liver. Int J Mol Med 34, 16471654.CrossRefGoogle ScholarPubMed
199. Colak, Y, Yesil, A, Mutlu, HH, et al. (2014) A potential treatment of non-alcoholic fatty liver disease with SIRT1 activators. J Gastrointest Liver Dis 23, 311319.Google ScholarPubMed
200. Gillum, MP, Kotas, ME, Erion, DM, et al. (2011) SirT1 regulates adipose tissue inflammation. Diabetes 60, 32353245.CrossRefGoogle ScholarPubMed
201. Herranz, D & Serrano, M (2010) SIRT1: recent lessons from mouse models. Nat Rev Cancer 10, 819823.CrossRefGoogle ScholarPubMed
202. Escande, C, Chini, CC, Nin, V, et al. (2010) Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice. J Clin Invest 120, 545558.CrossRefGoogle ScholarPubMed
203. Suter, MA, Chen, A, Burdine, MS, et al. (2012) A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J 26, 51065114.CrossRefGoogle ScholarPubMed
204. Colak, Y, Ozturk, O, Senates, E, et al. (2011) SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med Sci Monit 17, HY5HY9.CrossRefGoogle ScholarPubMed
205. Kim, HS, Patel, K, Muldoon-Jacobs, K, et al. (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 4152.CrossRefGoogle ScholarPubMed
206. Wang, RH, Sengupta, K, Li, C, et al. (2008) Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312323.CrossRefGoogle ScholarPubMed
207. Herranz, D, Muñoz-Martin, M, Canamero, M, et al. (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1, 3.CrossRefGoogle ScholarPubMed
208. Lu, SC, Alvarez, L, Huang, ZZ, et al. (2001) Methionine adenosyl transferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci U S A 98, 55605565.CrossRefGoogle Scholar
209. Martinez-Chantar, ML, Corrales, FJ, Martinez-Cruz, LA, et al. (2002) Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J 16, 12921294.CrossRefGoogle ScholarPubMed
210. Liao, YJ, Liu, SP, Lee, CM, et al. (2009) Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: implications of the gender disparity in liver cancer susceptibility. Int J Cancer 124, 816826.CrossRefGoogle ScholarPubMed
211. Lu, SC & Mato, JM (2012) S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92, 15151542.CrossRefGoogle Scholar
212. Wang, Z, Yao, H, Lin, S, et al. (2013) Transcriptional and epigenetic regulation of human microRNAs. Cancer Lett 331, 110.CrossRefGoogle ScholarPubMed
213. Finch, ML, Marquardt, JU, Yeoh, GC, et al. (2014) Regulation of microRNAs and their role in liver development, regeneration and disease. Int J Biochem Cell Biol 54, 288303.CrossRefGoogle ScholarPubMed
214. Ferreira, DM, Simão, AL, Rodrigues, CM, et al. (2014) Revisiting the metabolic syndrome and paving the way for microRNAs in non-alcoholic fatty liver disease. FEBS J 281, 25032524.CrossRefGoogle ScholarPubMed
215. Panera, N, Gnani, D, Crudele, A, et al. (2014) MicroRNAs as controlled systems and controllers in non-alcoholic fatty liver disease. World J Gastroenterol 20, 1507915086.CrossRefGoogle ScholarPubMed
216. Viré, E, Brenner, C, Deplus, R, et al. (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871874.CrossRefGoogle ScholarPubMed
217. Cao, R, Wang, L, Wang, H, et al. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 10391043.CrossRefGoogle ScholarPubMed
218. Vella, S, Gnani, D, Crudele, A, et al. (2013) EZH2 down-regulation exacerbates lipid accumulation and inflammation in in vitro and in vivo NAFLD. Int J Mol Sci 14, 2415424168.CrossRefGoogle ScholarPubMed
219. Estep, M, Armistead, D, Hossain, N, et al. (2010) Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 32, 487497.CrossRefGoogle ScholarPubMed
220. Cermelli, S, Ruggieri, A, Marrero, JA, et al. (2011) Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE 6, e23937.CrossRefGoogle ScholarPubMed
221. Tryndyak, VP, Latendresse, JR, Montgomery, B, et al. (2012) Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet. Toxicol Appl Pharmacol 262, 5259.CrossRefGoogle ScholarPubMed
222. Hulsmans, M, Van Dooren, E, Mathieu, C, et al. (2012) Decrease of miR-146b-5p in monocytes during obesity is associated with loss of the anti-inflammatory but not insulin signaling action of adiponectin. PLOS ONE 7, e32794.CrossRefGoogle Scholar
223. Balasubramanyam, M, Aravind, S, Gokulakrishnan, K, et al. (2011) Impaired miR-146a expression links subclinical inflammation and insulin resistance in type 2 diabetes. Mol Cell Biochem 351, 197205.CrossRefGoogle ScholarPubMed
224. Foley, NH & O’Neill, LA (2012) miR-107: a Toll-like receptor-regulated miRNA dysregulated in obesity and type II diabetes. J Leukoc Biol 92, 521527.CrossRefGoogle ScholarPubMed
225. Arner, E, Mejhert, N, Kulyté, A, et al. (2012) Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes 61, 19861993.CrossRefGoogle ScholarPubMed
226. Tsai, WC, Hsu, SD, Hsu, CS, et al. (2012) MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 122, 28842897.CrossRefGoogle Scholar
227. Hulsmans, M, de Keyzer, D, Holvoet, P (2011) MicroRNAs regulating oxidative stress and inflammation in relation to obesity and atherosclerosis. FASEB J 25, 25152527.CrossRefGoogle ScholarPubMed
228. Wang, B, Majumder, S, Nuovo, G, et al. (2009) Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 50, 11521161.CrossRefGoogle ScholarPubMed
229. Vinciguerra, M, Sgroi, A, Veyrat-Durebex, C, et al. (2009) Unsaturated fatty acids inhibit the expression of tumor suppressor hosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology 49, 11761184.CrossRefGoogle Scholar
230. Meng, F, Henson, R, Wehbe-Janek, H, et al. (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647658.CrossRefGoogle ScholarPubMed
231. Pogribny, IP, Starlard-Davenport, A, Tryndyak, VP, et al. (2010) Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab Invest 90, 14371446.CrossRefGoogle ScholarPubMed
232. Yan, XL, Jia, YL, Chen, L, et al. (2013) Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology 57, 22742286.CrossRefGoogle ScholarPubMed
233. Worm, J, Stenvang, J, Petri, A, et al. (2009) Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp β and down-regulation of G-CSF. Nucleic Acids Res 37, 57845792.CrossRefGoogle ScholarPubMed
234. Reddy, MA, Chen, Z, Park, JT, et al. (2014) Regulation of inflammatory phenotype in macrophages by a diabetes-induced long non-coding RNA. Diabetes 63, 42494261.CrossRefGoogle Scholar