Lipotoxicity and the gut-liver axis in NASH pathogenesis

Journal of Hepatology

Volumn 68, Issue 2, 2018, Pages 280-295

  Marra, Fabio ^a   Svegliati Baroni, Gianluca ^b  

^a UNIVERSITY OF FLORENCE   (Italy)

^b UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

Author keywords

Apoptosis; Ceramides; Fibroblast growth factor; Fibrosis; Free fatty acids; FXR; Inflammasome; Inflammation; JNK; Microbiota

Indexed keywords

BILE ACID; CELL NUCLEUS RECEPTOR; CERAMIDE; CHOLESTEROL; DEATH RECEPTOR; FATTY ACID; GASTROINTESTINAL HORMONE; LYSOPHOSPHATIDYLCHOLINE; PROTEIN BCL 2; STRESS ACTIVATED PROTEIN KINASE; TRIACYLGLYCEROL;

AUTOPHAGY; ENDOPLASMIC RETICULUM STRESS; EXOSOME; GLUCOTOXICITY; HUMAN; INTESTINE; INTESTINE FLORA; LIPOTOXICITY; LIVER; LIVER METABOLISM; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; APOPTOSIS; GASTROINTESTINAL TRACT; LIPID METABOLISM; METABOLISM;

APOPTOSIS; GASTROINTESTINAL TRACT; HUMANS; LIPID METABOLISM; LIVER; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS;

EID: 85037731368     PISSN: 01688278     EISSN: 16000641     Source Type: Journal    
DOI: 10.1016/j.jhep.2017.11.014     Document Type: Review

References (164)

1. Satapathy, S.K., Sanyal, A.J., Epidemiology and natural history of nonalcoholic fatty liver disease. Semin Liver Dis 35 (2015), 221–235.
2. Rinella, M.E., Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (2015), 2263–2273.
3. Dulai, P.S., Singh, S., Patel, J., Soni, M., Prokop, L.J., Younossi, Z., et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65 (2017), 1557–1565.
4. Caligiuri, A., Gentilini, A., Marra, F., Molecular pathogenesis of NASH. Int J Mol Sci, 17, 2016.
5. Ertunc, M.E., Hotamisligil, G.S., Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57 (2016), 2099–2114.
6. Fu, S., Watkins, S.M., Hotamisligil, G.S., The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15 (2012), 623–634.
7. Perry, R.J., Samuel, V.T., Petersen, K.F., Shulman, G.I., The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510 (2014), 84–91.
8. Lee, J.Y., Sohn, K.H., Rhee, S.H., Hwang, D., Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276 (2001), 16683–16689.
9. Youssef, O.A., Safran, S.A., Nakamura, T., Nix, D.A., Hotamisligil, G.S., Bass, B.L., Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U S A 112 (2015), 5023–5028.
10. Ozcan, L., Ergin, A.S., Lu, A., Chung, J., Sarkar, S., Nie, D., et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9 (2009), 35–51.
11. Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P.D., Backhed, F., Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab 22 (2015), 658–668.
12. Donnelly, K.L., Smith, C.I., Schwarzenberg, S.J., Jessurun, J., Boldt, M.D., Parks, E.J., Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115 (2005), 1343–1351.
13. Yamaguchi, K., Yang, L., McCall, S., Huang, J., Yu, X.X., Pandey, S.K., et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45 (2007), 1366–1374.
14. Papazyan, R., Sun, Z., Kim, Y.H., Titchenell, P.M., Hill, D.A., Lu, W., et al. Physiological suppression of lipotoxic liver damage by complementary actions of HDAC3 and SCAP/SREBP. Cell Metab 24 (2016), 863–874.
15. Wang, C., Zhao, Y., Gao, X., Li, L., Yuan, Y., Liu, F., et al. Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis. Hepatology 61 (2015), 870–882.
16. Wilson, C.G., Tran, J.L., Erion, D.M., Vera, N.B., Febbraio, M., Weiss, E.J., Hepatocyte-specific disruption of CD36 attenuates fatty liver and improves insulin sensitivity in HFD-fed mice. Endocrinology 157 (2016), 570–585.
17. Hirsova, P., Ibrahim, S.H., Gores, G.J., Malhi, H., Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 57 (2016), 1758–1770.
18. Ralston, J.C., Lyons, C.L., Kennedy, E.B., Kirwan, A.M., Roche, H.M., Fatty acids and NLRP3 inflammasome-mediated inflammation in metabolic tissues. Annu Rev Nutr 37 (2017), 77–102.
19. Li, Z.Z., Berk, M., McIntyre, T.M., Feldstein, A.E., Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J Biol Chem 284 (2009), 5637–5644.
20. Akazawa, Y., Cazanave, S., Mott, J.L., Elmi, N., Bronk, S.F., Kohno, S., et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J Hepatol 52 (2010), 586–593.
21. El-Badry, A.M., Graf, R., Clavien, P.A., Omega 3 – Omega 6: What is right for the liver?. J Hepatol 47 (2007), 718–725.
22. Puri, P., Baillie, R.A., Wiest, M.M., Mirshahi, F., Choudhury, J., Cheung, O., et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46 (2007), 1081–1090.
23. Sanyal, A.J., Abdelmalek, M.F., Suzuki, A., Cummings, O.W., Chojkier, M., EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 147 (2014), 377–384 e371.
24. Han, M.S., Park, S.Y., Shinzawa, K., Kim, S., Chung, K.W., Lee, J.H., et al. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res 49 (2008), 84–97.
25. Mota, M., Banini, B.A., Cazanave, S.C., Sanyal, A.J., Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 65 (2016), 1049–1061.
26. Chavez, J.A., Siddique, M.M., Wang, S.T., Ching, J., Shayman, J.A., Summers, S.A., Ceramides and glucosylceramides are independent antagonists of insulin signaling. J Biol Chem 289 (2014), 723–734.
27. Raichur, S., Wang, S.T., Chan, P.W., Li, Y., Ching, J., Chaurasia, B., et al. CerS2 haploinsufficiency inhibits beta-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab 20 (2014), 687–695.
28. Pagadala, M., Kasumov, T., McCullough, A.J., Zein, N.N., Kirwan, J.P., Role of ceramides in nonalcoholic fatty liver disease. Trends Endocrinol Metab 23 (2012), 365–371.
29. Xia, J.Y., Holland, W.L., Kusminski, C.M., Sun, K., Sharma, A.X., Pearson, M.J., et al. Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab 22 (2015), 266–278.
30. Ioannou, G.N., The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol Metab 27 (2016), 84–95.
31. Bellanti, F., Mitarotonda, D., Tamborra, R., Blonda, M., Iannelli, G., Petrella, A., et al. Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease. Free Radic Biol Med 75 (2014), S16–S17.
32. Ter Horst, K.W., Serlie, M.J., Fructose consumption, lipogenesis, and non-alcoholic fatty liver disease. Nutrients, 9, 2017.
33. Softic, S., Gupta, M.K., Wang, G.X., Fujisaka, S., O'Neill, B.T., Rao, T.N., et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest 127 (2017), 4059–4074.
34. Galluzzi, L., Vitale, I., Abrams, J.M., Alnemri, E.S., Baehrecke, E.H., Blagosklonny, M.V., et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19 (2012), 107–120.
35. Szegezdi, E., Logue, S.E., Gorman, A.M., Samali, A., Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7 (2006), 880–885.
36. Rutkowski, D.T., Wu, J., Back, S.H., Callaghan, M.U., Ferris, S.P., Iqbal, J., et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 15 (2008), 829–840.
37. Rius, B., Duran-Guell, M., Flores-Costa, R., Lopez-Vicario, C., Lopategi, A., Alcaraz-Quiles, J., et al. The specialized pro-resolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress. FASEB J 31 (2017), 5384–5398.
38. Malhi, H., Bronk, S.F., Werneburg, N.W., Gores, G.J., Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 281 (2006), 12093–12101.
39. Kodama, Y., Kisseleva, T., Iwaisako, K., Miura, K., Taura, K., De Minicis, S., et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 137 (2009), 1467–1477 e1465.
40. Cazanave, S.C., Mott, J.L., Elmi, N.A., Bronk, S.F., Werneburg, N.W., Akazawa, Y., et al. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J Biol Chem 284 (2009), 26591–26602.
41. Malhi, H., Barreyro, F.J., Isomoto, H., Bronk, S.F., Gores, G.J., Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56 (2007), 1124–1131.
42. Win, S., Than, T.A., Le, B.H., Garcia-Ruiz, C., Fernandez-Checa, J.C., Kaplowitz, N., Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol 62 (2015), 1367–1374.
43. Tomita, K., Kohli, R., MacLaurin, B.L., Hirsova, P., Guo, Q., Sanchez, L.H.G., et al. Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis. JCI Insight, 2, 2017.
44. Loomba, R., Lawitz, E., Mantry, P.S., Jayakumar, S., Caldwell, S.H., Arnold, H., et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology, 2017, 10.1002/hep.29514 in press.
45. Czabotar, P.E., Lessene, G., Strasser, A., Adams, J.M., Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15 (2014), 49–63.
46. Cazanave, S.C., Wang, X., Zhou, H., Rahmani, M., Grant, S., Durrant, D.E., et al. Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis. Cell Death Differ 21 (2014), 1303–1312.
47. Feldstein, A.E., Wieckowska, A., Lopez, A.R., Liu, Y.C., Zein, N.N., McCullough, A.J., Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50 (2009), 1072–1078.
48. Masuoka, H.C., Mott, J., Bronk, S.F., Werneburg, N.W., Akazawa, Y., Kaufmann, S.H., et al. Mcl-1 degradation during hepatocyte lipoapoptosis. J Biol Chem 284 (2009), 30039–30048.
49. Ratziu, V., Sheikh, M.Y., Sanyal, A.J., Lim, J.K., Conjeevaram, H., Chalasani, N., et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 55 (2012), 419–428.
50. Wiens, G.D., Glenney, G.W., Origin and evolution of TNF and TNF receptor superfamilies. Dev Comp Immunol 35 (2011), 1324–1335.
51. Malhi, H., Guicciardi, M.E., Gores, G.J., Hepatocyte death: a clear and present danger. Physiol Rev 90 (2010), 1165–1194.
52. Yamaguchi, H., Wang, H.G., CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279 (2004), 45495–45502.
53. Idrissova, L., Malhi, H., Werneburg, N.W., LeBrasseur, N.K., Bronk, S.F., Fingas, C., et al. TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. J Hepatol 62 (2015), 1156–1163.
54. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., et al. Autophagy regulates lipid metabolism. Nature 458 (2009), 1131–1135.
55. Maus, M., Cuk, M., Patel, B., Lian, J., Ouimet, M., Kaufmann, U., et al. Store-operated Ca2+ entry controls induction of lipolysis and the transcriptional reprogramming to lipid metabolism. Cell Metab 25 (2017), 698–712.
56. Li, S., Dou, X., Ning, H., Song, Q., Wei, W., Zhang, X., et al. Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity. Hepatology 66 (2017), 936–952.
57. Hernandez-Gea, V., Ghiassi-Nejad, Z., Rozenfeld, R., Gordon, R., Fiel, M.I., Yue, Z., et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142 (2012), 938–946.
58. Sunny, N.E., Bril, F., Cusi, K., Mitochondrial adaptation in nonalcoholic fatty liver disease: novel mechanisms and treatment strategies. Trends Endocrinol Metab 28 (2017), 250–260.
59. Martel, C., Allouche, M., Esposti, D.D., Fanelli, E., Boursier, C., Henry, C., et al. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology 57 (2013), 93–102.
60. Gariani, K., Menzies, K.J., Ryu, D., Wegner, C.J., Wang, X., Ropelle, E.R., et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63 (2016), 1190–1204.
61. Li, Z., Berk, M., McIntyre, T.M., Gores, G.J., Feldstein, A.E., The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology 47 (2008), 1495–1503.
62. Hamlin, A.N., Basford, J.E., Jaeschke, A., Hui, D.Y., LRP1 protein deficiency exacerbates palmitate-induced steatosis and toxicity in hepatocytes. J Biol Chem 291 (2016), 16610–16619.
63. Aubert, J., Begriche, K., Knockaert, L., Robin, M.A., Fromenty, B., Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol 35 (2011), 630–637.
64. Hall, Z., Bond, N.J., Ashmore, T., Sanders, F., Ament, Z., Wang, X., et al. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology 65 (2017), 1165–1180.
65. Sanyal, A.J., Chalasani, N., Kowdley, K.V., McCullough, A., Diehl, A.M., Bass, N.M., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362 (2010), 1675–1685.
66. Szabo, G., Momen-Heravi, F., Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. Nat Rev Gastroenterol Hepatol 14 (2017), 455–466.
67. Hirsova, P., Ibrahim, S.H., Krishnan, A., Verma, V.K., Bronk, S.F., Werneburg, N.W., et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150 (2016), 956–967.
68. Machado, M.V., Diehl, A.M., Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology 150 (2016), 1769–1777.
69. Rangwala, F., Guy, C.D., Lu, J., Suzuki, A., Burchette, J.L., Abdelmalek, M.F., et al. Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol 224 (2011), 401–410.
70. Navarro, L.A., Wree, A., Povero, D., Berk, M.P., Eguchi, A., Ghosh, S., et al. Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis. J Hepatol 62 (2015), 412–420.
71. Huang, W., Metlakunta, A., Dedousis, N., Zhang, P., Sipula, I., Dube, J.J., et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59 (2010), 347–357.
72. Shi, H., Kokoeva, M.V., Inouye, K., Tzameli, I., Yin, H., Flier, J.S., TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116 (2006), 3015–3025.
73. Min, H.K., Maruyama, H., Jang, B.K., Shimada, M., Mirshahi, F., Ren, S., et al. Suppression of IGF binding protein-3 by palmitate promotes hepatic inflammatory responses. FASEB J 30 (2016), 4071–4082.
74. Natarajan, S.K., Ingham, S.A., Mohr, A.M., Wehrkamp, C.J., Ray, A., Roy, S., et al. Saturated free fatty acids induce cholangiocyte lipoapoptosis. Hepatology 60 (2014), 1942–1956.
75. Teratani, T., Tomita, K., Suzuki, T., Oshikawa, T., Yokoyama, H., Shimamura, K., et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 142 (2012), 152–164 e110.
76. Backhed, F., Ley, R.E., Sonnenburg, J.L., Peterson, D.A., Gordon, J.I., Host-bacterial mutualism in the human intestine. Science 307 (2005), 1915–1920.
77. Neish, A.S., Microbes in gastrointestinal health and disease. Gastroenterology 136 (2009), 65–80.
78. Betrapally, N.S., Gillevet, P.M., Bajaj, J.S., Changes in the intestinal microbiome and alcoholic and nonalcoholic liver diseases: causes or effects?. Gastroenterology 150 (2016), 1745–1755 e1743.
79. Jandhyala, S.M., Talukdar, R., Subramanyam, C., Vuyyuru, H., Sasikala, M., Nageshwar, Reddy D., Role of the normal gut microbiota. World J Gastroenterol 21 (2015), 8787–8803.
80. Sanduzzi Zamparelli, M., Compare, D., Coccoli, P., Rocco, A., Nardone, O.M., Marrone, G., et al. The metabolic role of gut microbiota in the development of nonalcoholic fatty liver disease and cardiovascular disease. Int J Mol Sci, 17, 2016.
81. Aron-Wisnewsky, J., Dore, J., Clement, K., The importance of the gut microbiota after bariatric surgery. Nat Rev Gastroenterol Hepatol 9 (2012), 590–598.
82. Sommer, F., Backhed, F., The gut microbiota–masters of host development and physiology. Nat Rev Microbiol 11 (2013), 227–238.
83. Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R., Gordon, J.I., An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444 (2006), 1027–1031.
84. Machado, M.V., Cortez-Pinto, H., Diet, microbiota, obesity, and NAFLD: a dangerous quartet. Int J Mol Sci, 17, 2016, 481.
85. den Besten, G., Bleeker, A., Gerding, A., van Eunen, K., Havinga, R., van Dijk, T.H., et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARgamma-dependent switch from lipogenesis to fat oxidation. Diabetes 64 (2015), 2398–2408.
86. den Besten, G., Gerding, A., van Dijk, T.H., Ciapaite, J., Bleeker, A., van Eunen, K., et al. Protection against the metabolic syndrome by guar gum-derived short-chain fatty acids depends on peroxisome proliferator-activated receptor gamma and glucagon-like peptide-1. PLoS One, 10, 2015, e0136364.
87. den Besten, G., van Eunen, K., Groen, A.K., Venema, K., Reijngoud, D.J., Bakker, B.M., The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54 (2013), 2325–2340.
88. Leung, C., Rivera, L., Furness, J.B., Angus, P.W., The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 13 (2016), 412–425.
89. Rahman, K., Desai, C., Iyer, S.S., Thorn, N.E., Kumar, P., Liu, Y., et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 151 (2016), 733–746 e712.
90. Pendyala, S., Walker, J.M., Holt, P.R., A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 142 (2012), 1100–1101 e1102.
91. Peterson, L.W., Artis, D., Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14 (2014), 141–153.
92. Heymann, F., Tacke, F., Immunology in the liver–from homeostasis to disease. Nat Rev Gastroenterol Hepatol 13 (2016), 88–110.
93. Guo, H., Callaway, J.B., Ting, J.P., Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21 (2015), 677–687.
94. Mencin, A., Kluwe, J., Schwabe, R.F., Toll-like receptors as targets in chronic liver diseases. Gut 58 (2009), 704–720.
95. Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410 (2001), 1099–1103.
96. Szabo, G., Iracheta-Vellve, A., Inflammasome activation in the liver: Focus on alcoholic and non-alcoholic steatohepatitis. Clin Res Hepatol Gastroenterol 39 (2015), S18–S23.
97. Mridha, A.R., Wree, A., Robertson, A.A.B., Yeh, M.M., Johnson, C.D., Van Rooyen, D.M., et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol 66 (2017), 1037–1046.
98. Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W.Z., Strowig, T., et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482 (2012), 179–185.
99. Wree, A., McGeough, M.D., Pena, C.A., Schlattjan, M., Li, H., Inzaugarat, M.E., et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med 92 (2014), 1069–1082.
100. Vandanmagsar, B., Youm, Y.H., Ravussin, A., Galgani, J.E., Stadler, K., Mynatt, R.L., et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17 (2011), 179–188.
101. Stienstra, R., van Diepen, J.A., Tack, C.J., Zaki, M.H., van de Veerdonk, F.L., Perera, D., et al. Inflammasome is a central player in the induction of obesity and insulin resistance. PNAS 108 (2011), 15324–15329.
102. Zaki, M.H., Boyd, K.L., Vogel, P., Kastan, M.B., Lamkanfi, M., Kanneganti, T.D., The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32 (2010), 379–391.
103. Elinav, E., Strowig, T., Kau, A.L., Henao-Mejia, J., Thaiss, C.A., Booth, C.J., et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145 (2011), 745–757.
104. Pierantonelli, I., Rychlicki, C., Agostinelli, L., Giordano, D.M., Gaggini, M., Fraumene, C., et al. Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD. Sci Rep, 7, 2017, 12200.
105. De Minicis, S., Rychlicki, C., Agostinelli, L., Saccomanno, S., Candelaresi, C., Trozzi, L., et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59 (2014), 1738–1749.
106. Tailford, L.E., Crost, E.H., Kavanaugh, D., Juge, N., Mucin glycan foraging in the human gut microbiome. Front Genet, 6, 2015, 81.
107. Rodriguez-Pineiro, A.M., Johansson, M.E., The colonic mucus protection depends on the microbiota. Gut Microbes 6 (2015), 326–330.
108. Zhu, L., Baker, S.S., Gill, C., Liu, W., Alkhouri, R., Baker, R.D., et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57 (2013), 601–609.
109. Boursier, J., Mueller, O., Barret, M., Machado, M., Fizanne, L., Araujo-Perez, F., et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63 (2016), 764–775.
110. Marchesi, J.R., Adams, D.H., Fava, F., Hermes, G.D., Hirschfield, G.M., Hold, G., et al. The gut microbiota and host health: a new clinical frontier. Gut 65 (2016), 330–339.
111. Del Chierico, F., Nobili, V., Vernocchi, P., Russo, A., Stefanis, C., Gnani, D., et al. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 65 (2017), 451–464.
112. Loomba, R., Seguritan, V., Li, W., Long, T., Klitgord, N., Bhatt, A., et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab 25 (2017), 1054–1062 e1055.
113. Putignani, L., Alisi, A., Nobili, V., Pediatric NAFLD: the future role of patient-tailored probiotics therapy. J Pediatr Gastroenterol Nutr 63 (2016), S6–S8.
114. Alisi, A., Bedogni, G., Baviera, G., Giorgio, V., Porro, E., Paris, C., et al. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 39 (2014), 1276–1285.
115. DeFronzo, R.A., Ferrannini, E., Groop, L., Henry, R.R., Herman, W.H., Holst, J.J., et al. Type 2 diabetes mellitus. Nat Rev Dis Primers, 1, 2015, 15019.
116. Gastaldelli, A., Gaggini, M., DeFronzo, R., Glucose kinetics: an update and novel insights into its regulation by glucagon and GLP-1. Curr Opin Clin Nutr Metab Care 20 (2017), 300–309.
117. Nauck, M.A., Meier, J.J., The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol 4 (2016), 525–536.
118. Campbell, J.E., Drucker, D.J., Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 17 (2013), 819–837.
119. Sandoval, D.A., D'Alessio, D.A., Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev 95 (2015), 513–548.
120. Prigeon, R.L., Quddusi, S., Paty, B., D'Alessio, D.A., Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285 (2003), E701–E707.
121. Gastaldelli, A., Gaggini, M., Daniele, G., Ciociaro, D., Cersosimo, E., Tripathy, D., et al. Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study. Hepatology 64 (2016), 2028–2037.
122. Daniele, G., Iozzo, P., Molina-Carrion, M., Lancaster, J., Ciociaro, D., Cersosimo, E., et al. Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system. Diabetes 64 (2015), 3406–3412.
123. Seghieri, M., Rebelos, E., Gastaldelli, A., Astiarraga, B.D., Casolaro, A., Barsotti, E., et al. Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia 56 (2013), 156–161.
124. Ding, X., Saxena, N.K., Lin, S., Gupta, N.A., Anania, F.A., Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43 (2006), 173–181.
125. Gupta, N.A., Mells, J., Dunham, R.M., Grakoui, A., Handy, J., Saxena, N.K., et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51 (2010), 1584–1592.
126. Mells, J.E., Fu, P.P., Sharma, S., Olson, D., Cheng, L., Handy, J.A., et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol 302 (2012), G225–G235.
127. Svegliati-Baroni, G., Saccomanno, S., Rychlicki, C., Agostinelli, L., De Minicis, S., Candelaresi, C., et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 31 (2011), 1285–1297.
128. Armstrong, M.J., Gaunt, P., Aithal, G.P., Barton, D., Hull, D., Parker, R., et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387 (2016), 679–690.
129. Armstrong, M.J., Hull, D., Guo, K., Barton, D., Hazlehurst, J.M., Gathercole, L.L., et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol 64 (2016), 399–408.
130. FDA. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm491062.htm, 2016.
131. Dube, P.E., Brubaker, P.L., Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators. Am J Physiol Endocrinol Metab 293 (2007), E460–E465.
132. Henao-Mejia, J., Elinav, E., Thaiss, C.A., Flavell, R.A., The intestinal microbiota in chronic liver disease. Adv Immunol 117 (2013), 73–97.
133. Schaap, F.G., Trauner, M., Jansen, P.L., Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 11 (2014), 55–67.
134. Kuipers, F., Bloks, V.W., Groen, A.K., Beyond intestinal soap–bile acids in metabolic control. Nat Rev Endocrinol 10 (2014), 488–498.
135. Kurdi, P., Kawanishi, K., Mizutani, K., Yokota, A., Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J Bacteriol 188 (2006), 1979–1986.
136. Ryan, K.K., Tremaroli, V., Clemmensen, C., Kovatcheva-Datchary, P., Myronovych, A., Karns, R., et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509 (2014), 183–188.
137. Parseus, A., Sommer, N., Sommer, F., Caesar, R., Molinaro, A., Stahlman, M., et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 66 (2017), 429–437.
138. Yuan, L., Bambha, K., Bile acid receptors and nonalcoholic fatty liver disease. World J Hepatol 7 (2015), 2811–2818.
139. Watanabe, M., Houten, S.M., Wang, L., Moschetta, A., Mangelsdorf, D.J., Heyman, R.A., et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113 (2004), 1408–1418.
140. Pineda Torra, I., Claudel, T., Duval, C., Kosykh, V., Fruchart, J.C., Staels, B., Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17 (2003), 259–272.
141. Savkur, R.S., Bramlett, K.S., Michael, L.F., Burris, T.P., Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor. Biochem Biophys Res Commun 329 (2005), 391–396.
142. Fuchs, C.D., Traussnigg, S.A., Trauner, M., Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis 36 (2016), 69–86.
143. Arab, J.P., Karpen, S.J., Dawson, P.A., Arrese, M., Trauner, M., Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65 (2017), 350–362.
144. Zhang, Y., Lee, F.Y., Barrera, G., Lee, H., Vales, C., Gonzalez, F.J., et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 103 (2006), 1006–1011.
145. Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C.L., McDonald, J.G., et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2 (2005), 217–225.
146. Alvarez-Sola, G., Uriarte, I., Latasa, M.U., Fernandez-Barrena, M.G., Urtasun, R., Elizalde, M., et al. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut 66 (2017), 1818–1828.
147. Tomlinson, E., Fu, L., John, L., Hultgren, B., Huang, X., Renz, M., et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143 (2002), 1741–1747.
148. Fu, L., John, L.M., Adams, S.H., Yu, X.X., Tomlinson, E., Renz, M., et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145 (2004), 2594–2603.
149. Kir, S., Beddow, S.A., Samuel, V.T., Miller, P., Previs, S.F., Suino-Powell, K., et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331 (2011), 1621–1624.
150. Neuschwander-Tetri, B.A., Loomba, R., Sanyal, A.J., Lavine, J.E., Van Natta, M.L., Abdelmalek, M.F., et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385 (2015), 956–965.
151. Wiest, R., Albillos, A., Trauner, M., Bajaj, J.S., Jalan, R., Targeting the gut-liver axis in liver disease. J Hepatol 67 (2017), 1084–1103.
152. Uriarte, I., Latasa, M.U., Carotti, S., Fernandez-Barrena, M.G., Garcia-Irigoyen, O., Elizalde, M., et al. Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer 136 (2015), 2469–2475.
153. Nicholes, K., Guillet, S., Tomlinson, E., Hillan, K., Wright, B., Frantz, G.D., et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 160 (2002), 2295–2307.
154. Zhou, M., Luo, J., Chen, M., Yang, H., Learned, R.M., DePaoli, A.M., et al. Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J Hepatol 66 (2017), 1182–1192.
155. Takeda, S., Kadowaki, S., Haga, T., Takaesu, H., Mitaku, S., Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett 520 (2002), 97–101.
156. Watanabe, M., Houten, S.M., Mataki, C., Christoffolete, M.A., Kim, B.W., Sato, H., et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439 (2006), 484–489.
157. Thomas, C., Gioiello, A., Noriega, L., Strehle, A., Oury, J., Rizzo, G., et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10 (2009), 167–177.
158. van Nierop, F.S., Scheltema, M.J., Eggink, H.M., Pols, T.W., Sonne, D.P., Knop, F.K., et al. Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol 5 (2017), 224–233.
159. Wahlstrom, A., Sayin, S.I., Marschall, H.U., Backhed, F., Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24 (2016), 41–50.
160. Sayin, S.I., Wahlstrom, A., Felin, J., Jantti, S., Marschall, H.U., Bamberg, K., et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17 (2013), 225–235.
161. Li, F., Jiang, C., Krausz, K.W., Li, Y., Albert, I., Hao, H., et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun, 4, 2013, 2384.
162. Jiang, C., Xie, C., Li, F., Zhang, L., Nichols, R.G., Krausz, K.W., et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125 (2015), 386–402.
163. Trabelsi, M.S., Daoudi, M., Prawitt, J., Ducastel, S., Touche, V., Sayin, S.I., et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun, 6, 2015, 7629.
164. Jiang, C., Xie, C., Lv, Y., Li, J., Krausz, K.W., Shi, J., et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun, 6, 2015, 10166.