Skip to main content Accessibility help

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

  • Sabrina Campisano (a1), Anabela La Colla (a1), Stella M. Echarte (a1) and Andrea N. Chisari (a1)


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.


Corresponding author

*Corresponding author: Dr Andrea N. Chisari, fax +54 223 475 2426, email


Hide All
1. Barker, DJ (2004) The developmental origins of chronic adult disease. Acta Paediatr 93, 2633.
2. Brumbaugh, DE & Friedman, JE (2014) Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 75, 140147.
3. Gallego-Durán, R & Romero-Gómez, M (2015) Epigenetic mechanisms in non-alcoholic fatty liver disease: an emerging field. World J Hepatol 7, 24972502.
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.
5. Singer, C, Stancu, P, Coşoveanu, S, et al. (2014) Non-alcoholic fatty liver disease in children. Curr Health Sci J 40, 170176.
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.
7. Victora, CG, Adair, L, Fall, C, et al. (2008) Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371, 340357.
8. Hales, CN & Barker, DJP (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595601.
9. Gluckman, PD & Hanson, MA (2004) The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15, 183187.
10. Barker, DJ, Eriksson, JG & Forsén, T (2002) Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 31, 12351239.
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.
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.
13. Ross, MG & Beall, MH (2008) Adult sequelae of intrauterine growth restriction. Semin Perinatol 32, 213218.
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.
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.
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.
17. Whitaker, RC (2004) Predicting preschooler obesity at birth: the role of maternal obesity in early pregnancy. Pediatrics 114, e29e36.
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.
19. Correia-Branco, A, Keating, E & Martel, F (2015) Maternal undernutrition and fetal developmental programming of obesity: the glucocorticoid connection. Reprod Sci 22, 138145.
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.
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.
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.
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.
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.
25. Dietrich, P & Hellerbrand, C (2014) Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol 28, 637653.
26. Byrne, CD & Targher, GJ (2015) NAFLD: a multisystem disease. J Hepatol 62, Suppl. 1, S47S64.
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.
28. Farazi, PA & De Pinho, RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6, 674687.
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.
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.
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.
32. Stickel, F & Hellerbrand, C (2010) Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut 59, 13031307.
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.
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.
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.
36. Malhi, H, Bronk, SF, Werneburg, NW, et al. (2006) Free fatty acids induce JNK dependent hepatocyte lipoapoptosis. J Biol Chem 281, 1209312101.
37. Gallagher, EJ & Le Roith, D (2011) Mini review: IGF, insulin, and cancer. Endocrinology 152, 25462551.
38. Jang, H & Serra, C (2014) Nutrition, epigenetics, and diseases. Clin Nutr Res 3, 18.
39. Lee, JH, Friso, S & Choi, SW (2014) Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients 6, 33033325.
40. Franco, R, Schoneveld, O, Georgakilas, AG, et al. (2008) Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett 266, 611.
41. Lahtz, C & Pfeifer, GP (2011) Epigenetic changes of DNA repair genes in cancer. J Mol Cell Biol 3, 5158.
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.
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.
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.
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.
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.
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.
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.
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.
50. Sun, C, Fan, JG, Qiao, L (2015) Potential epigenetic mechanism in non-alcoholic fatty liver disease. Int J Mol Sci 16, 51615179.
51. Giby, VG & Ajith, TA (2014) Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol 6, 570579.
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.
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.
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.
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.
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.
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.
58. Ling, C & Groop, L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58, 27182725.
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.
60. Feige, J & Auwerx, J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20, 303309.
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.
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.
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.
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.
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.
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.
67. Gueant, JL, Namour, F, Gueant-Rodriguez, RM, et al. (2013) Folate and fetal programming: a play in epigenomics? Trends Endocrinol Metab 24, 279289.
68. Portha, B, Fournier, A, Kioon, MD, et al. (2014) Early environmental factors, alteration of epigenetic marks and metabolic disease susceptibility. Biochimie 97, 115.
69. Lynn, FC (2009) Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol Metab 20, 452459.
70. Lakner, AM, Bonkovsky, HL & Schrum, LW (2011) microRNAs: fad or future of liver disease. World J Gastroenterol 17, 25362542.
71. Cheung, O, Puri, P, Eicken, C, et al. (2008) Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48, 18101820.
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.
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.
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.
75. Wen, J & Friedman, JR (2012) miR-122 regulates hepatic lipid metabolism and tumor suppression. J Clin Invest 122, 27732776.
76. Seki, E & Brenner, DA (2008) Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48, 322335.
77. Machado, M, Marques-Vidal, P & Cortez-Pinto, H (2006) Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 45, 600606.
78. Gregor, MF & Hotamisligil, GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29, 415445.
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.
80. Robinson, MW, Harmon, C & O’Farrelly, C (2016) Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 13, 267276.
81. Smedsrod, B, De Bleser, PJ, Braet, F, et al. (1994) Cell biology of liver endothelial and Kupffer cells. Gut 35, 15091516.
82. Bilzer, M, Roggel, F & Gerbes, AL (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26, 11751186.
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.
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.
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.
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.
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.
88. Sica, A & Mantovani, A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122, 787795.
89. Biswas, SK & Mantovani, A (2012) Orchestration of metabolism by macrophages. Cell Metab 15, 432437.
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.
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.
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.
93. Bonizzi, G & Karin, M (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25, 280288.
94. Lawrence, T & Gilroy, DW (2007) Chronic inflammation: a failure of resolution? Int J Exp Pathol 88, 8594.
95. Hagemann, T, Lawrence, T, McNeish, I, et al. (2008) “Re-educating” tumor-associated macrophages by targeting NF-κB. J Exp Med 205, 12611268.
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.
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.
98. Han, MS, Jung, DY, Morel, C, et al. (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339, 218222.
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.
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.
101. Ekihiro, S & Brenner, DA (2008) Toll-like receptors and adaptor molecules in liver disease: updates. Hepatology 48, 322335.
102. Aoyama, T, Paik, YH & Seki, E (2010) Toll-like receptor signalling and liver fibrosis. Gastroenterol Res Pract 2010, 192543.
103. Iimuro, Y & Fujimoto, J (2010) TLRs, NF-κB, JNK, and liver regeneration. Gastroenterol Res Pract 2010, 598109.
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.
105. Rivera, CA, Gaskin, L, Allman, M, et al. (2010) Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis. BMC Gastroenterol 10, 52.
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.
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.
108. Martinon, F, Mayor, A & Tschopp, J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27, 229265.
109. Pedra, JH, Cassel, SL & Sutterwala, FS (2009) Sensing pathogens and danger signals by the inflammasome. Curr Opin Immunol 21, 1016.
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.
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.
112. Eun-Kyeong, J, Jin Kyung, K, Dong-Min, S, et al. (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 13, 148159.
113. Doherty, DG (2016) Antigen-presenting cell function in the tolerogenic liver environment. J Autoimmun 66, 6075.
114. Rahman, AH & Aloman, C (2013) Dendritic cells and liver fibrosis. Biochim Biophys Acta 1832, 9981004.
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.
116. Heymann, F & Take, F (2016) Immunology of the liver – from homeostasis to disease. Nat Rev Gastroenteol Hepatol 13, 88110.
117. Thomson, AW & Knolle, PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10, 753766.
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.
119. Henning, JR, Graffeo, CS, Rehman, A, et al. (2013) Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58, 589602.
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.
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.
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.
123. Bernsmeier, C & Albano, E (2017) Liver dendritic cells and NAFLD evolution: a remaining open issue. J Hepatol 66, 11201122.
124. Dutertre, CA, Wang, LF & Ginhoux, F (2014) Aligning bona fide dendritic cell populations across species. Cell Immunol 291, 310.
125. Kelly, A, Fahey, R, Fletcher, JM, et al. (2014) CD141+ myeloid dendritic cells are enriched in healthy human liver. J Hepatol 60, 135142.
126. Gabrilovich, DI & Nagaraj, S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9, 162174.
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.
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.
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.
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.
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.
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.
133. Schneider, C, Teufel, A, Yevsa, T, et al. (2012) Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61, 17331743.
134. Hammerich, L & Tacke, F (2015) Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis. World J Gastrointest Pathophysiol 6, 4350.
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.
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.
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.
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.
139. Ganz, M & Szabo, G (2013) Immune and inflammatory pathways in NASH. Hepatol Int 7, 771781.
140. Tian, Z, Chen, Y & Gao, B (2013) Natural killer cells in liver disease. Hepatology 57, 16541662.
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.
142. Krizhanovsky, V, Yon, M, Dickins, RA, et al. (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657667.
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.
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.
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.
146. Norris, S, Collins, C, Doherty, DG, et al. (1998) Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 28, 8490.
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.
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.
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.
150. Sell, H, Habich, C & Eckel, J (2012) Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 8, 709716.
151. Brunt, EM (2010) Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7, 195203.
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.
153. Boujedidi, H, Robert, O, Bignon, A, et al. (2015) CXCR4 dysfunction in nonalcoholic steatohepatitis in mice and patients. Clin Sci (Lond) 128, 257267.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
164. Ramadori, G & Saile, B (2004) Portal tract fibrogenesis in the liver. Lab Invest 84, 153159.
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.
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.
167. Elpek, GO (2014) Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J Gastroenterol 20, 72607276.
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.
169. Seki, E, De Minicis, S, Osterreicher, CH, et al. (2007) TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 13, 13241332.
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.
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.
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.
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.
174. Lleo, A & Invernizzi, P (2013) Apotopes and innate immune system: novel players in the primary biliary cirrhosis scenario. Dig Liver Dis 45, 630636.
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.
176. Crispe, IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27, 147163.
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.
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.
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.
180. Mann, J, Chu, DC, Maxwell, A, et al. (2010) MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705714.
181. Zeybel, M, Hardy, T, Wong, YK, et al. (2012) Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med 18, 13691377.
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.
183. Wang, X, Zhu, H, Snieder, H, et al. (2010) Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Med 8, 87.
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.
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.
186. Yang, X, Wang, X, Liu, D, et al. (2014) Epigenetic regulation of macrophage polarization by DNA methyl transferase 3b. Mol Endocrinol 28, 565574.
187. Herath, NI, Leggett, BA & MacDonald, GA (2006) Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 21, 1521.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
200. Gillum, MP, Kotas, ME, Erion, DM, et al. (2011) SirT1 regulates adipose tissue inflammation. Diabetes 60, 32353245.
201. Herranz, D & Serrano, M (2010) SIRT1: recent lessons from mouse models. Nat Rev Cancer 10, 819823.
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.
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.
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.
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.
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.
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.
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.
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.
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.
211. Lu, SC & Mato, JM (2012) S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92, 15151542.
212. Wang, Z, Yao, H, Lin, S, et al. (2013) Transcriptional and epigenetic regulation of human microRNAs. Cancer Lett 331, 110.
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.
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.
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.
216. Viré, E, Brenner, C, Deplus, R, et al. (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871874.
217. Cao, R, Wang, L, Wang, H, et al. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 10391043.
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.
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.
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.
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.
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.
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.
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.
225. Arner, E, Mejhert, N, Kulyté, A, et al. (2012) Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes 61, 19861993.
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.
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.
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.
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.
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.
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.
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.
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.
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.


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

  • Sabrina Campisano (a1), Anabela La Colla (a1), Stella M. Echarte (a1) and Andrea N. Chisari (a1)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed