The role of macrophages in obesity-driven chronic liver disease

Journal of Leukocyte Biology

Volumn 99, Issue 5, 2016, Pages 693-698

  Devisscher, Lindsey ^a   Verhelst, Xavier ^a   Colle, Isabelle ^a   Van Vlierberghe, Hans ^a   Geerts, Anja ^a  

^a GHENT UNIVERSITY   (Belgium)

Author keywords

Kupffer cell; Monocyte; Nonalcoholic fatty liver disease; Steatohepatitis

Indexed keywords

FATTY ACID; INTERLEUKIN 1BETA; INTERLEUKIN 6; MONOCYTE CHEMOTACTIC PROTEIN 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PLATELET DERIVED GROWTH FACTOR; REACTIVE OXYGEN METABOLITE; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR; VASCULOTROPIN;

ANTIINFLAMMATORY ACTIVITY; CELL INFILTRATION; CHRONIC INFLAMMATION; CHRONIC LIVER DISEASE; CYTOKINE PRODUCTION; DISEASE COURSE; DNA POLYMORPHISM; EXPERIMENTAL STEATOHEPATITIS; EXTRACELLULAR MATRIX; HEPATITIS; HOMEOSTASIS; HUMAN; KUPFFER CELL; LIPID PEROXIDATION; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FATTY DEGENERATION; MACROPHAGE; MACROPHAGE FUNCTION; METABOLIC SYNDROME X; MONOCYTE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; OVERNUTRITION; PRIORITY JOURNAL; REVIEW; SEDENTARY LIFESTYLE; STEATOSIS; STELLATE CELL; TISSUE INJURY; ANIMAL; BIOLOGICAL MODEL; CHRONIC DISEASE; COMPLICATION; LIVER DISEASES; PATHOLOGY;

ANIMALS; CHRONIC DISEASE; DISEASE PROGRESSION; HUMANS; LIVER DISEASES; MACROPHAGES; MODELS, BIOLOGICAL; OBESITY;

EID: 84964734732     PISSN: 07415400     EISSN: 19383673     Source Type: Journal    
DOI: 10.1189/jlb.5RU0116-016R     Document Type: Review

References (89)

1. Schulz, C., Gomez Perdiguero, E., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W., Frampton, J., Liu, K. J., Geissmann, F. (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86-90.
2. Yona, S., Kim, K.-W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Viukov, S., Guilliams, M., Misharin, A., Hume, D. A., Perlman, H., Malissen, B., Zelzer, E., Jung, S. (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis published correction is available at http://dx.doi.org/10.1016/j.immuni.2013.05.008.Immunity 38, 79-91.
3. Tacke, F., Zimmermann, H. W. (2014) Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090-1096.
4. Scott, C. L., Henri, S., Guilliams, M. (2014) Mononuclear phagocytes of the intestine, the skin, and the lung. Immunol. Rev. 262, 9-24
5. Lavin, Y., Mortha, A., Rahman, A., Merad, M. (2015) Regulation of macrophage development and function in peripheral tissues. Nat. Rev. Immunol. 15, 731-744.
6. Murray, P. J., Wynn, T. A. (2011) Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723-737.
7. Coulon, S., Heindryckx, F., Geerts, A., Van Steenkiste, C., Colle, I., Van Vlierberghe, H. (2011) Angiogenesis in chronic liver disease and its complications. Liver Int. 31, 146-162.
8. Baeck, C., Wei, X., Bartneck, M., Fech, V, Heymann, F., Gassler, N, Hittatiya, K., Eulberg, D., Luedde, T., Trautwein, C., Tacke, F. (2014) Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology 59, 1060-1072.
9. Ehling, J., Bartneck, M., Wei, X., Gremse, F., Fech, V., Möckel, D., Baeck, C., Hittatiya, K., Eulberg, D., Luedde, T., Kiessling, F., Trautwein, C., Lammers, T., Tacke, F. (2014) CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63, 1960-1971.
10. Trautwein, C., Friedman, S. L., Schuppan, D., Pinzani, M. (2015) Hepatic fibrosis: concept to treatment. J. Hepatol. 62(1:, Suppl) S15-S24.
11. Paradis, V., Zalinski, S., Chelbi, E., Guedj, N., Degos, F., Vilgrain, V., Bedossa, P., Belghiti, J. (2009) Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49, 851-859.
12. Michelotti, G. A., Machado, M. V., Diehl, A. M. (2013) NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656-665.
13. Gadd, V. L., Skoien, R., Powell, E. E., Fagan, K. J., Winterford, C., Horsfall, L., Irvine, K., Clouston, A. D. (2014) The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 59, 1393-1405.
14. Chatzigeorgiou, A., Chavakis, T. 2015. Immune cells and metabolism. In Handbook of Experimental Pharmacology. (J. E. Barrett, V. Flockerzi, M. A. Frohman, P. Geppetti, F. B. Hofmann, M. C. Michel, C. P. Page, A. M. Thorburn, K. Wang, eds.) Springer, Berlin Heidelberg, 1-29.
15. Huang, S., Rutkowsky, J. M., Snodgrass, R. G., Ono-Moore, K. D., Schneider, D. A., Newman, J. W., Adams, S. H., Hwang, D. H. (2012) Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J. Lipid Res. 53, 2002-2013.
16. Jia, L., Vianna, C. R., Fukuda, M., Berglund, E. D., Liu, C., Tao, C., Sun, K., Liu, T., Harper, M. J., Lee, C. E., Lee, S., Scherer, P. E., Elmquist, J. K. (2014) Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 3878.
17. Cinti, S., Mitchell, G., Barbatelli, G., Murano, I., Ceresi, E., Faloia, E., Wang, S., Fortier, M., Greenberg, A. S., Obin, M. S. (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347-2355.
18. Wernstedt Asterholm, I., Tao, C., Morley, T. S., Wang, Q. A., Delgado- Lopez, F., Wang, Z. V., Scherer, P. E. (2014) Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103-118.
19. Matzinger, P. (1994) Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991-1045.
20. Kono, H., Rock, K. L. (2008) How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279-289.
21. Mosser, D. M., Edwards, J. P. (2008) Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958-969.
22. Bastard, J.-P., Maachi, M., Lagathu, C., Kim, M. J., Caron, M., Vidal, H., Capeau, J., Feve, B. (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17, 4-12.
23. Lumeng, C. N., Bodzin, J. L., Saltiel, A. R. (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175-184.
24. Lumeng, C. N., Deyoung, S. M., Bodzin, J. L., Saltiel, A. R. (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56, 16-23.
25. Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., Kitazawa, S., Miyachi, H., Maeda, S., Egashira, K., Kasuga, M. (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494-1505.
26. Patsouris, D., Li, P.-P., Thapar, D., Chapman, J., Olefsky, J. M., Neels, J. G. (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301-309.
27. McGarry, J. D., Foster, D. W. (1980) Regulation of hepatic fatty acid oxidation and ketone body production. Annu. Rev. Biochem. 49, 395-420.
28. Postic, C., Girard, J. (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 118, 829-838.
29. Stanton, M. C., Chen, S.-C., Jackson, J. V., Rojas-Triana, A., Kinsley, D., Cui, L., Fine, J. S., Greenfeder, S., Bober, L. A., Jenh, C. H. (2011) Inflammatory signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J. Inflamm. (Lond.) 8, 8.
30. du Plessis, J., van Pelt, J., Korf, H., Mathieu, C., van der Schueren, B., Lannoo, M., Oyen, T., Topal, B., Fetter, G., Nayler, S., van der Merwe, T., Windmolders, P., Van Gaal, L., Verrijken, A., Hubens, G., Gericke, M., Cassiman, D., Francque, S., Nevens, F., van der Merwe, S. (2015) Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 149, 635-48.e14.
31. James, O. F., Day, C. P. (1998) Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J. Hepatol. 29, 495-501.
32. Tilg, H., Moschen, A. R. (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836-1846.
33. Stienstra, R., Saudale, F., Duval, C., Keshtkar, S., Groener, J. E. M., van Rooijen, N., Staels, B., Kersten, S., Müller, M. (2010) Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 51, 511-522.
34. Miura, K., Kodama, Y., Inokuchi, S., Schnabl, B., Aoyama, T., Ohnishi, H., Olefsky, J. M., Brenner, D. A., Seki, E. (2010) Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139, 323-34.e7.
35. Negrin, K. A., Roth Flach, R. J., DiStefano, M. T., Matevossian, A., Friedline, R. H., Jung, D., Kim, J. K., Czech, M. P. (2014) IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One 9, e107265.
36. Huang, W., Metlakunta, A., Dedousis, N., Zhang, P., Sipula, I., Dube, J. J., Scott, D. K., O’Doherty, R. M. (2010) Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59, 347-357.
37. Navarro, L. A., Wree, A., Povero, D., Berk, M. P., Eguchi, A., Ghosh, S., Papouchado, B. G., Erzurum, S. C., Feldstein, A. E. (2015) Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis. J. Hepatol. 62, 412-420.
38. Ganz, M., Bukong, T. N., Csak, T., Saha, B., Park, J.-K., Ambade, A., Kodys, K., Szabo, G. (2015) Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fatcholesterol- sugar diet model in mice. J. Transl. Med. 13, 193-239.
39. Bieghs, V., Trautwein, C. (2014) Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease. Hepatobiliary Surg. Nutr. 3, 377-385.
40. Leroux, A., Ferrere, G., Godie, V., Cailleux, F., Renoud, M.-L., Gaudin, F., Naveau, S., Prévot, S., Makhzami, S., Perlemuter, G., Cassard-Doulcier, A. M. (2012) Toxic lipids stored by Kupffer cells correlates with their proinflammatory phenotype at an early stage of steatohepatitis. J. Hepatol. 57, 141-149.
41. Bieghs, V., Wouters, K., van Gorp, P. J., Gijbels, M. J. J., de Winther, M. P. J., Binder, C. J., Lütjohann, D., Febbraio, M., Moore, K. J., van Bilsen, M., Hofker, M. H., Shiri-Sverdlov, R. (2010) Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. Gastroenterology 138, 2477-2486, e3.
42. Bieghs, V., van Gorp, P. J., Walenbergh, S. M. A., Gijbels, M. J., Verheyen, F., Buurman, W. A., Briles, D. E., Hofker, M. H., Binder, C. J., Shiri- Sverdlov, R. (2012) Specific immunization strategies against oxidized lowdensity lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology 56, 894-903.
43. Bieghs, V., Verheyen, F., van Gorp, P. J., Hendrikx, T., Wouters, K., Lütjohann, D., Gijbels, M. J. J., Febbraio, M., Binder, C. J., Hofker, M. H., Shiri-Sverdlov, R. (2012) Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells. PLoS One 7, e34378.
44. Bieghs, V., Walenbergh, S. M. A., Hendrikx, T., van Gorp, P. J., Verheyen, F., Olde Damink, S. W., Masclee, A. A., Koek, G. H., Hofker, M. H., Binder, C. J., Shiri-Sverdlov, R. (2013) Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int. 33, 1056-1061.
45. Tosello-Trampont, A.-C., Landes, S. G., Nguyen, V., Novobrantseva, T. I., Hahn, Y. S. (2012) Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-a production. J. Biol. Chem. 287, 40161-40172.
46. Karlmark, K. R., Weiskirchen, R., Zimmermann, H. W., Gassler, N., Ginhoux, F., Weber, C., Merad, M., Luedde, T., Trautwein, C., Tacke, F. (2009) Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261-274.
47. Seki, E., de Minicis, S., Inokuchi, S., Taura, K., Miyai, K., van Rooijen, N., Schwabe, R. F., Brenner, D. A. (2009) CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185-197.
48. Mitchell, C., Couton, D., Couty, J.-P., Anson, M., Crain, A.-M., Bizet, V., Rénia, L., Pol, S., Mallet, V., Gilgenkrantz, H. (2009) Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am. J. Pathol. 174, 1766-1775.
49. Zimmermann, H. W., Seidler, S., Nattermann, J., Gassler, N., Hellerbrand, C., Zernecke, A., Tischendorf, J. J. W., Luedde, T., Weiskirchen, R., Trautwein, C., Tacke, F. (2010) Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One 5, e11049.
50. Miura, K., Yang, L., van Rooijen, N., Ohnishi, H., Seki, E. (2012) Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1310-G1321.
51. Haukeland, J. W., Damås, J. K., Konopski, Z., Løberg, E. M., Haaland, T., Goverud, I., Torjesen, P. A., Birkeland, K., Bjøro, K., Aukrust, P. (2006) Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J. Hepatol. 44, 1167-1174.
52. Kassel, K. M., Guo, G. L., Tawfik, O., Luyendyk, J. P. (2010) Monocyte chemoattractant protein-1 deficiency does not affect steatosis or inflammation in livers of mice fed a methionine-choline-deficient diet. Lab. Invest. 90, 1794-1804.
53. Zigmond, E., Samia-Grinberg, S., Pasmanik-Chor, M., Brazowski, E., Shibolet, O., Halpern, Z., Varol, C. (2014) Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury. J. Immunol. 193, 344-353.
54. Wan, J., Benkdane, M., Teixeira-Clerc, F., Bonnafous, S., Louvet, A., Lafdil, F., Pecker, F., Tran, A., Gual, P., Mallat, A., Lotersztajn, S., Pavoine, C. (2014) M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59, 130-142.
55. Kang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B., Lee, C. H. (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485-495.
56. Odegaard, J. I., Ricardo-Gonzalez, R. R., Red Eagle, A., Vats, D., Morel, C. R., Goforth, M. H., Subramanian, V., Mukundan, L., Ferrante, A. W., Chawla, A. (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496-507.
57. Staels, B., Rubenstrunk, A., Noel, B., Rigou, G., Delataille, P., Millatt, L. J., Baron, M., Lucas, A., Tailleux, A., Hum, D. W., Ratziu, V., Cariou, B., Hanf, R. (2013) Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941-1952.
58. Cariou, B., Hanf, R., Lambert-Porcheron, S., Zaïr, Y., Sauvinet, V., Noël, B., Flet, L., Vidal, H., Staels, B., Laville, M. (2013) Dual peroxisome proliferator-activated receptor a/d agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923-2930.
59. Lanthier, N. (2015) Targeting Kupffer cells in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: why and how? World J. Hepatol. 7, 2184-2188.
60. Bataller, R., Brenner, D. A. (2005) Liver fibrosis. J. Clin. Invest. 115, 209-218.
61. Karlmark, K. R., Wasmuth, H. E., Trautwein, C., Tacke, F. (2008) Chemokine-directed immune cell infiltration in acute and chronic liver disease. Expert Rev. Gastroenterol. Hepatol. 2, 233-242.
62. De Minicis, S., Seki, E., Uchinami, H., Kluwe, J., Zhang, Y., Brenner, D. A., Schwabe, R. F. (2007) Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 132, 1937-1946.
63. Pradere, J.-P., Kluwe, J., De Minicis, S., Jiao, J.-J., Gwak, G.-Y., Dapito, D. H., Jang, M. K., Guenther, N. D., Mederacke, I., Friedman, R., Dragomir, A. C., Aloman, C., Schwabe, R. F. (2013) Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58, 1461-1473.
64. Mederacke, I., Hsu, C. C., Troeger, J. S., Huebener, P., Mu, X., Dapito, D. H., Pradere, J. P., Schwabe, R. F. (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823.
65. Duffield, J. S., Forbes, S. J., Constandinou, C. M., Clay, S., Partolina, M., Vuthoori, S., Wu, S., Lang, R., Iredale, J. P. (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56-65.
66. Fallowfield, J. A., Mizuno, M., Kendall, T. J., Constandinou, C. M., Benyon, R. C., Duffield, J. S., Iredale, J. P. (2007) Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288-5295.
67. Pellicoro, A., Aucott, R. L., Ramachandran, P., Robson, A. J., Fallowfield, J. A., Snowdon, V. K., Hartland, S. N., Vernon, M., Duffield, J. S., Benyon, R. C., Forbes, S. J., Iredale, J. P. (2012) Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology 55, 1965-1975.
68. Ramachandran, P., Pellicoro, A., Vernon, M. A., Boulter, L., Aucott, R. L., Ali, A., Hartland, S. N., Snowdon, V. K., Cappon, A., Gordon-Walker, T. T., Williams, M. J., Dunbar, D. R., Manning, J. R., van Rooijen, N., Fallowfield, J. A., Forbes, S. J., Iredale, J. P. (2012) Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl. Acad. Sci. USA 109, E3186-E3195.
69. Polesel, J., Zucchetto, A., Montella, M., Dal Maso, L., Crispo, A., La Vecchia, C., Serraino, D., Franceschi, S., Talamini, R. (2009) The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann. Oncol. 20, 353-357.
70. Stickel, F., Hellerbrand, C. (2010) Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut 59, 1303-1307.
71. Maeda, S., Kamata, H., Luo, J.-L., Leffert, H., Karin, M. (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990.
72. Balkwill, F. (2006) TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 25, 409-416.
73. Lu, H., Ouyang, W., Huang, C. (2006) Inflammation, a key event in cancer development. Mol. Cancer Res. 4, 221-233.
74. Hill-Baskin, A. E., Markiewski, M. M., Buchner, D. A., Shao, H., DeSantis, D., Hsiao, G., Subramaniam, S., Berger, N. A., Croniger, C., Lambris, J. D., Nadeau, J. H. (2009) Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum. Mol. Genet. 18, 2975-2988.
75. Park, E. J., Lee, J. H., Yu, G.-Y., He, G., Ali, S. R., Holzer, R. G., Osterreicher, C. H., Takahashi, H., Karin, M. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197-208.
76. Hu, Z.-W., Luo, H.-B., Xu, Y.-M., Guo, J.-W., Deng, X.-L., Tong, Y.-W., Tang, X. (2009) Tumor necrosis factor-alpha gene promoter polymorphisms in Chinese patients with nonalcoholic fatty liver diseases. Acta Gastroenterol. Belg. 72, 215-221.
77. Valenti, L., Al-Serri, A., Daly, A. K., Galmozzi, E., Rametta, R., Dongiovanni, P., Nobili, V., Mozzi, E., Roviaro, G., Vanni, E., Bugianesi, E., Maggioni, M., Fracanzani, A. L., Fargion, S., Day, C. P. (2010) Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209-1217.
78. Zhou, Y.-J., Li, Y.-Y., Nie, Y.-Q., Yang, H., Zhan, Q., Huang, J., Shi, S. L., Lai, X. B., Huang, H. L. (2010) Influence of polygenetic polymorphisms on the susceptibility to non-alcoholic fatty liver disease of Chinese people. J. Gastroenterol. Hepatol. 25, 772-777.
79. Wei, Y., Liu, F., Li, B., Chen, X., Ma, Y., Yan, L., Wen, T., Xu, M., Wang, W., Yang, J. (2011) Polymorphisms of tumor necrosis factor-alpha and hepatocellular carcinoma risk: a HuGE systematic review and metaanalysis. Dig. Dis. Sci. 56, 2227-2236.
80. Maeda, S. (2010) NF-kB, JNK, and TLR signaling pathways in hepatocarcinogenesis. Gastroenterol. Res. Pract. 2010, 367694.
81. Sakurai, T., Maeda, S., Chang, L., Karin, M. (2006) Loss of hepatic NFkappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl. Acad. Sci. USA 103, 10544-10551.
82. Chang, Q., Zhang, Y., Beezhold, K. J., Bhatia, D., Zhao, H., Chen, J., Castranova, V., Shi, X., Chen, F. (2009) Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J. Hepatol. 50, 323-333.
83. Capece, D., Fischietti, M., Verzella, D., Gaggiano, A., Cicciarelli, G., Tessitore, A., Zazzeroni, F., Alesse, E. (2013) The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumorassociated macrophages. BioMed Res. Int. 2013, 187204.
84. Feng, D. Y., Shen, M., Zheng, H., Cheng, R. X. (2000) [Relationship between vascular endothelial growth factor expression and microvessel density in hepatocellular carcinomas and their surrounding liver tissue] (in Chinese). Hunan Yi Ke Da Xue Xue Bao 25, 132-134.
85. Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., Sethi, G. (2006) Inflammation and cancer: how hot is the link? Biochem. Pharmacol. 72, 1605-1621.
86. Szlosarek, P., Charles, K. A., Balkwill, F. R. (2006) Tumour necrosis factor-alpha as a tumour promoter. Eur. J. Cancer 42, 745-750.
87. Mantovani, A., Schioppa, T., Porta, C., Allavena, P., Sica, A. (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 25, 315-322.
88. Hammam, O., Mahmoud, O., Zahran, M., Sayed, A., Salama, R., Hosny, K., Farghly, A. (2013) A possible role for TNF-a in coordinating inflammation and angiogenesis in chronic liver disease and hepatocellular carcinoma. Gastrointest. Cancer Res. 6, 107-114.
89. Heindryckx, F., Gerwins, P. (2015) Targeting the tumor stroma in hepatocellular carcinoma. World J. Hepatol. 7, 165-176.