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01-06-2014 | Fatty Liver Disease (SA Harrison and J George, Section Editors)

Mechanisms of Liver Injury in Non-Alcoholic Steatohepatitis

Authors: Caroline C. Duwaerts, Jacquelyn J. Maher

Published in: Current Hepatology Reports | Issue 2/2014

Abstract

Non-alcoholic steatohepatitis (NASH) is a disorder marked by alterations in hepatic lipid homeostasis as well as liver injury in the form of cell death, inflammation and fibrosis. Research into the pathophysiology of NASH is dynamic. New concepts from the fields of cell biology, microbiology, immunology and genetics are being tested for their applicability to NASH; discoveries in each of these areas are enriching our understanding of this complex disease. This review summarizes how recent developments from the bench and bedside are merging with more traditional concepts to reshape our view of NASH pathogenesis. Highlights include human studies that emphasize the role of de novo lipogenesis in NASH and experimental work uncovering a role for the inflammasome in NASH. Genetic predispositions to NASH are being clarified, and intestinal microbiome is emerging as a determinant of fatty liver. These unique ideas are now taking their place within an integrated picture of NASH pathogenesis.

Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.PubMed

Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998;114(4):842–5.PubMed

Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46. doi:10.1002/hep.24001.PubMed

Attie AD, Scherer PE. Adipocyte metabolism and obesity. J Lipid Res. 2009;50(Suppl):S395–9. doi:10.1194/jlr.R800057-JLR200.PubMedCentralPubMed

Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev. 2012;249(1):218–38. doi:10.1111/j.1600-065X.2012.01151.x.PubMedCentralPubMed

Matherly SC, Puri P. Mechanisms of simple hepatic steatosis: not so simple after all. Clin Liver Dis. 2012;16(3):505–24. doi:10.1016/j.cld.2012.05.005.PubMed

Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621–37.PubMedCentralPubMed

Endo M, Masaki T, Seike M, Yoshimatsu H. TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood). 2007;232(5):614–21.

Clement S, Juge-Aubry C, Sgroi A, Conzelmann S, Pazienza V, Pittet-Cuenod B, et al. Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes. Hepatology. 2008;48(3):799–807. doi:10.1002/hep.22404.PubMed

10.

Barrows BR, Parks EJ. Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. J Clin Endocrinol Metab. 2006;91(4):1446–52. doi:10.1210/jc.2005-1709.PubMed

11.

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–51. doi:10.1172/JCI23621.PubMedCentralPubMed

12.•

Lambert JE. Ramos-Roman MA. Parks EJ. Increased de novo Lipogenesis is a Distinct Characteristic of Individuals with Nonalcoholic Fatty Liver Disease. Gastroenterology: Browning JD; 2013. doi:10.1053/j.gastro.2013.11.049. Elegant human study demonstrating that hepatic steatosis in persons with NAFLD is largely due to enhanced hepatic DNL.

13.

Chen X, Iqbal N, Boden G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest. 1999;103(3):365–72. doi:10.1172/JCI5479.PubMedCentralPubMed

14.

Li S, Brown MS, Goldstein JL. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A. 2010;107(8):3441–6. doi:10.1073/pnas.0914798107.PubMedCentralPubMed

15.

Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109(9):1125–31.PubMedCentralPubMed

16.

Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A. 2003;100(21):12027–32. doi:10.1073/pnas.1534923100.PubMedCentralPubMed

17.

Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A. 1999;96(24):13656–61.PubMedCentralPubMed

18.

Su Q, Tsai J, Xu E, Qiu W, Bereczki E, Santha M, et al. Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance. Hepatology. 2009;50(1):77–84.PubMed

19.

Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest. 2009;119(5):1201–15. doi:10.1172/JCI37007.PubMedCentralPubMed

20.

Hudgins LC, Parker TS, Levine DM, Hellerstein MK. A dual sugar challenge test for lipogenic sensitivity to dietary fructose. J Clin Endocrinol Metab. 2011;96(3):861–8. doi:10.1210/jc.2010-2007.PubMedCentralPubMed

21.

Lecoultre V, Egli L, Carrel G, Theytaz F, Kreis R, Schneiter P, et al. Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans. Obesity (Silver Spring). 2013;21(4):782–5. doi:10.1002/oby.20377.

22.

Parks EJ, Skokan LE, Timlin MT, Dingfelder CS. Dietary sugars stimulate fatty acid synthesis in adults. J Nutr. 2008;138(6):1039–46.PubMedCentralPubMed

23.

Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119(5):1322–34.PubMedCentralPubMed

24.

Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(6):1961–71. doi:10.1002/hep.23535.PubMedCentralPubMed

25.

Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48(6):993–9. doi:10.1016/j.jhep.2008.02.011.PubMedCentralPubMed

26.

Jump DB, Clarke SD. Regulation of gene expression by dietary fat. Annu Rev Nutr. 1999;19:63–90.PubMed

27.

Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell. 2005;120(2):261–73.PubMed

28.

Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009;136(5):1552–60. doi:10.1053/j.gastro.2009.01.048.PubMedCentralPubMed

29.

Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281(17):12093–101. doi:10.1074/jbc.M510660200.PubMed

30.

Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006;43(1):163–72. doi:10.1002/hep.20999.PubMed

31.

Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology. 2009;49(1):87–96.PubMedCentralPubMed

32.

Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007;46(4):1081–90. doi:10.1002/hep.21763.PubMed

33.

Cazanave SC, Mott JL, Elmi NA, Bronk SF, Werneburg NW, Akazawa Y, et al. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J Biol Chem. 2009;284(39):26591–602.PubMedCentralPubMed

34.

Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287(5453):664–6.PubMed

35.

Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010;140(3):338–48. doi:10.1016/j.cell.2010.01.001.PubMedCentralPubMed

36.

Sharma M, Urano F, Jaeschke A. Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes. J Hepatol. 2012;56(1):192–8. doi:10.1016/j.jhep.2011.03.019.PubMedCentralPubMed

37.

Holzer RG, Park EJ, Li N, Tran H, Chen M, Choi C, et al. Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell. 2011;147(1):173–84. doi:10.1016/j.cell.2011.08.034.PubMedCentralPubMed

38.

Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481(7381):278–86. doi:10.1038/nature10759.PubMed

39.

Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology. 2011;54(1):133–44. doi:10.1002/hep.24341.PubMed

40.

Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation and fibrosis. Hepatology. 2013. doi:10.1002/hep.26592.

41.

Denes A, Lopez-Castejon G, Brough D. Caspase-1: is IL-1 just the tip of the ICEberg? Cell Death Dis. 2012;3:e338. doi:10.1038/cddis.2012.86.PubMedCentralPubMed

42.

Dixon LJ, Flask CA, Papouchado BG, Feldstein AE, Nagy LE. Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One. 2013;8(2):e56100. doi:10.1371/journal.pone.0056100.PubMedCentralPubMed

43.

Han MS, Park SY, Shinzawa K, Kim S, Chung KW, Lee JH, et al. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res. 2008;49(1):84–97.PubMed

44.

Kakisaka K, Cazanave SC, Fingas CD, Guicciardi ME, Bronk SF, Werneburg NW, et al. Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis. Am J Physiol Gastrointest Liver Physiol. 2012;302(1):G77–84. doi:10.1152/ajpgi.00301.2011.PubMedCentralPubMed

45.

Pagadala M, Kasumov T, McCullough AJ, Zein NN, Kirwan JP. Role of ceramides in nonalcoholic fatty liver disease. Trends Endocrinol Metab. 2012;23(8):365–71. doi:10.1016/j.tem.2012.04.005.PubMedCentralPubMed

46.

Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 2006;4(3):185–98. doi:10.1016/j.cmet.2006.07.006.PubMed

47.

Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab. 1998;83(8):2907–10. doi:10.1210/jcem.83.8.5026.PubMed

48.

Katsuki A, Sumida Y, Murashima S, Murata K, Takarada Y, Ito K, et al. Serum levels of tumor necrosis factor-alpha are increased in obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1998;83(3):859–62. doi:10.1210/jcem.83.3.4618.PubMed

49.

Min HK, Kapoor A, Fuchs M, Mirshahi F, Zhou H, Maher J, et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012;15(5):665–74. doi:10.1016/j.cmet.2012.04.004.PubMedCentralPubMed

50.

Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology. 2013;58(4):1497–507. doi:10.1002/hep.26226.PubMed

51.

Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011;14(6):804–10. doi:10.1016/j.cmet.2011.11.004.PubMedCentralPubMed

52.

Iozzo P, Bucci M, Roivainen A, Nagren K, Jarvisalo MJ, Kiss J, et al. Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals. Gastroenterology. 2010;139(3):e1–6. doi:10.1053/j.gastro.2010.05.039.PubMed

53.

Crescenzo R, Bianco F, Falcone I, Coppola P, Liverini G, Iossa S. Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Eur J Nutr. 2013;52(2):537–45. doi:10.1007/s00394-012-0356-y.PubMed

54.

Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378(2):259–68. doi:10.1006/abbi.2000.1829.PubMed

55.

Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion. 2006;6(1):1–28. doi:10.1016/j.mito.2005.10.004.PubMed

56.

Perez-Carreras M, Del Hoyo P, Martin MA, Rubio JC, Martin A, Castellano G, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38(4):999–1007. doi:10.1053/jhep.2003.50398.PubMed

57.

Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med. 2012;52(1):59–69. doi:10.1016/j.freeradbiomed.2011.10.003.PubMed

58.

Baumgardner JN, Shankar K, Hennings L, Badger TM, Ronis MJ. A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G27–38.PubMed

59.

Chalasani N, Gorski JC, Asghar MS, Asghar A, Foresman B, Hall SD, et al. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology. 2003;37(3):544–50. doi:10.1053/jhep.2003.50095.PubMed

60.

Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol. 2011;35(10):630–7. doi:10.1016/j.clinre.2011.04.015.PubMed

61.

Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–72. doi:10.1053/j.gastro.2012.09.008.PubMed

62.

Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12(5):408–15. doi:10.1038/ni.2022.PubMed

63.

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–72. doi:10.2337/db06-1491.PubMed

64.

Szabo G, Velayudham A, Romics Jr L, Mandrekar P. Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. Alcohol Clin Exp Res. 2005;29(11 Suppl):140S–5.PubMed

65.

Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47(4):571–9. doi:10.1016/j.jhep.2007.04.019.PubMedCentralPubMed

66.

Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139(1):323–34 e7. doi:10.1053/j.gastro.2010.03.052.PubMed

67.•

Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology. 2013;57(2):577–89. doi:10.1002/hep.26081. Study demonstrating that simultaneous exposure of Kupffer cells to TLR2 ligands and palmitate activates the inflammasome in these cells and contributes to NASH pathogenesis.PubMedCentralPubMed

68.

Imamura M, Tsutsui H, Yasuda K, Uchiyama R, Yumikura-Futatsugi S, Mitani K, et al. Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice. J Hepatol. 2009;51(2):333–41. doi:10.1016/j.jhep.2009.03.027.PubMed

69.

Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, et al. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology. 2010;51(2):511–22. doi:10.1002/hep.23337.PubMed

70.

Petrasek J, Dolganiuc A, Csak T, Kurt-Jones EA, Szabo G. Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice. Gastroenterology. 2011;140(2):697–708 e4. doi:10.1053/j.gastro.2010.08.020.PubMedCentralPubMed

71.

Leroux A, Ferrere G, Godie V, Cailleux F, Renoud ML, Gaudin F, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol. 2012;57(1):141–9. doi:10.1016/j.jhep.2012.02.028.PubMed

72.

Lanthier N, Molendi-Coste O, Cani PD, van Rooijen N, Horsmans Y, Leclercq IA. Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet. FASEB J. 2011;25(12):4301–11. doi:10.1096/fj.11-189472.PubMed

73.

Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J Biol Chem. 2012;287(48):40161–72. doi:10.1074/jbc.M112.417014.PubMedCentralPubMed

74.

Duwaerts CC, Gehring S, Cheng CW, van Rooijen N, Gregory SH. Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury. Liver Int. 2013;33(2):255–65. doi:10.1111/liv.12048.PubMedCentralPubMed

75.

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95. doi:10.1172/JCI59643.PubMedCentralPubMed

76.

Maina V, Sutti S, Locatelli I, Vidali M, Mombello C, Bozzola C, et al. Bias in macrophage activation pattern influences non-alcoholic steatohepatitis (NASH) in mice. Clin Sci (Lond). 2012;122(11):545–53. doi:10.1042/CS20110366.

77.

Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2013. doi:10.1002/hep.26607.

78.

Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7(6):496–507. doi:10.1016/j.cmet.2008.04.003.PubMedCentralPubMed

79.

Mandal P, Pratt BT, Barnes M, McMullen MR, Nagy LE. Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J Biol Chem. 2011;286(15):13460–9. doi:10.1074/jbc.M110.204644.PubMedCentralPubMed

80.

Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54(4):1217–26. doi:10.1002/hep.24524.PubMed

81.

Jiang JX, Mikami K, Venugopal S, Li Y, Torok NJ. Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. J Hepatol. 2009;51(1):139–48. doi:10.1016/j.jhep.2009.03.024.PubMedCentralPubMed

82.

Witek RP, Stone WC, Karaca FG, Syn WK, Pereira TA, Agboola KM, et al. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology. 2009;50(5):1421–30. doi:10.1002/hep.23167.PubMed

83.

Anstee QM, Concas D, Kudo H, Levene A, Pollard J, Charlton P, et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J Hepatol. 2010;53(3):542–50. doi:10.1016/j.jhep.2010.03.016.PubMed

84.

Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 2013;58(4):1461–73. doi:10.1002/hep.26429.PubMed

85.

Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13(11):1324–32.PubMed

86.

Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55(3):415–24. doi:10.1136/gut.2005.071118.PubMedCentralPubMed

87.

Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, et al. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol. 2011;300(3):G433–41. doi:10.1152/ajpgi.00163.2009.PubMedCentralPubMed

88.

Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302(11):G1310–21. doi:10.1152/ajpgi.00365.2011.PubMedCentralPubMed

89.

Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology. 2002;35(4):762–71. doi:10.1053/jhep.2002.32029.PubMedCentralPubMed

90.

Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784–92. doi:10.1172/JCI29126.PubMedCentralPubMed

91.

Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol. 2005;166(6):1655–69. doi:10.1016/S0002-9440(10)62476-5.PubMedCentralPubMed

92.

Marra F, Navari N, Vivoli E, Galastri S, Provenzano A. Modulation of liver fibrosis by adipokines. Dig Dis. 2011;29(4):371–6. doi:10.1159/000329799.PubMed

93.

Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5):1585–92. doi:10.1053/j.gastro.2009.01.050.PubMedCentralPubMed

94.

Wagenknecht LE, Scherzinger AL, Stamm ER, Hanley AJ, Norris JM, Chen YD, et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring). 2009;17(6):1240–6. doi:10.1038/oby.2009.4.

95.

Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–5. doi:10.1038/ng.257.PubMedCentralPubMed

96.

Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7(3):e1001324. doi:10.1371/journal.pgen.1001324.PubMedCentralPubMed

97.

Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53(6):1883–94. doi:10.1002/hep.24283.PubMed

98.

Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012;15(5):691–702. doi:10.1016/j.cmet.2012.04.008.PubMedCentralPubMed

99.

Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem. 2011;286(43):37085–93. doi:10.1074/jbc.M111.290114.PubMedCentralPubMed

100.

Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122(11):4130–44. doi:10.1172/JCI65179.PubMedCentralPubMed

101.

Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(4):1209–17. doi:10.1002/hep.23622.PubMed

102.

Krawczyk M, Grunhage F, Zimmer V, Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. J Hepatol. 2011;55(2):299–306. doi:10.1016/j.jhep.2010.10.042.PubMed

103.

Burza MA, Pirazzi C, Maglio C, Sjoholm K, Mancina RM, Svensson PA, et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis. 2012;44(12):1037–41. doi:10.1016/j.dld.2012.05.006.PubMed

104.

Hernaez R, McLean J, Lazo M, Brancati FL, Hirschhorn JN, Borecki IB, et al. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third national health and nutrition examination survey. Clin Gastroenterol Hepatol. 2013;11(9):1183–90 e2. doi:10.1016/j.cgh.2013.02.011.PubMed

105.

Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013;19(29):5219–38.PubMedCentralPubMed

106.

Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–23. doi:10.1073/pnas.0407076101.PubMedCentralPubMed

107.

Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104(3):979–84. doi:10.1073/pnas.0605374104.PubMedCentralPubMed

108.

Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635–8. doi:10.1126/science.1110591.PubMedCentralPubMed

109.

Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105–8. doi:10.1126/science.1208344.PubMedCentralPubMed

110.

Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–3. doi:10.1038/4441022a.PubMed

111.

Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY, et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009;137(5):1716–24 e1-2. doi:10.1053/j.gastro.2009.08.042.PubMedCentralPubMed

112.

Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102(31):11070–5. doi:10.1073/pnas.0504978102.PubMedCentralPubMed

113.

Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4. doi:10.1038/nature07540.PubMedCentralPubMed

114.

Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470–81. doi:10.2337/db07-1403.PubMed

115.•

Harley IT, Stankiewicz TE, Giles DA, Softic S, Flick LM, Cappelletti M, et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology. 2013. doi:10.1002/hep.26746. Novel animal study implicating certain types of gut bacteria in the pathogenesis of NASH via induction of IL-17.

116.

Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 2000;119(5):1340–7.PubMed

117.

Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877–87. doi:10.1002/hep.22848.PubMed

118.

Volynets V, Kuper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, et al. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2012;57(7):1932–41. doi:10.1007/s10620-012-2112-9.PubMed

119.

Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57(2):601–9. doi:10.1002/hep.26093.PubMed

120.

Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013;58(1):120–7. doi:10.1002/hep.26319.PubMed

121.

Iacono A, Raso GM, Canani RB, Calignano A, Meli R. Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. J Nutr Biochem. 2011;22(8):699–711. doi:10.1016/j.jnutbio.2010.10.002.PubMed

122.

Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L. Systematic review with meta-analysis: non-alcoholic steatohepatitis - a case for personalised treatment based on pathogenic targets. Aliment Pharmacol Ther. 2014;39(1):3–14. doi:10.1111/apt.12543.PubMed

Title: Mechanisms of Liver Injury in Non-Alcoholic Steatohepatitis
Authors: Caroline C. Duwaerts
Jacquelyn J. Maher
Publication date: 01-06-2014
Publisher: Springer US
Published in: Current Hepatology Reports / Issue 2/2014
Electronic ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-014-0224-8

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