NAFLD and NASH are complex conditions that involve derangements of lipid metabolism, cellular integrity, immune homeostasis, and tissue repair. Although they are abnormalities affecting the liver, NAFLD and NASH result from pathophysiologic processes that occur within and outside the liver. To develop a comprehensive understanding of the evolution of fatty liver disease, one must view the liver as a component of an integrated metabolic network that takes signals from the adipose tissue, intestine, pancreas, and brain. One must also consider that the disease process is influenced by genetic background, environmental factors, and personal behavior, all of which come together to regulate, or dysregulate, liver homeostasis. This chapter summarizes the pathophysiologic processes that lead to NAFLD and NASH. It begins with a discussion of abnormalities related to obesity that prime the liver to accumulate fat. Thereafter, the focus shifts to processes inside and outside the liver that perpetuate and accentuate hepatic steatosis. The second half of the chapter addresses the pathogenesis of liver injury in NASH. Here the discussion begins with a summary of cell death mechanisms in NASH and follows with sections devoted to hepatic inflammation, fibrosis, and cancer. Because NAFLD and NASH are so closely related, and because the disease does not always begin with “simple” steatosis and then evolve to steatohepatitis, the mechanistic distinction between the two entities is sometimes blurred. For the moment, the factors that prompt some individuals to develop hepatic steatosis while others develop full-blown NASH remain incompletely understood.


Nonalcoholic fatty liver disease, NAFLD Nonalcoholic steatohepatitis, NASH Endoplasmic reticulum (ER) stress Apoptosis Necroptosis Inflammasome Cytokine Kupffer cell 



Apoptosis-associated speck-like protein containing a caspase activation and recruitment domain


Acidic sphingomyelinase


Activating transcription factor 6


Brain and muscle aryl-hydrocarbon receptor nuclear translocator-like


Cannabinoid receptor 2


C-C chemokine ligand 2


C-EBP homologous protein


Carbohydrate response element-binding protein


Circadian locomotor output cycles kaput




Proto-oncogene tyrosine-protein kinase




Damage-associated molecular pattern




De novo lipogenesis


EGF receptor


Endoplasmic reticulum


Fas/CD95 receptor


Fas ligand


Fasting-induced adipocyte factor


Fatty acid transporter 5


Forkhead box O1


Farnesoid X receptor


Hepatocyte growth factor




Inositol-requiring enzyme 1


Jun N-terminal kinase


Lysophosphatidic acid acyltransferase


Mixed lineage kinase domain-like protein


Mitochondrial respiratory chain


Mammalian target of rapamycin


Nonalcoholic fatty liver disease


Nonalcoholic steatohepatitis




NOD-like receptor proteins


Nucleotide-binding oligomerization domain


Pathogen-associated molecular pattern




RNA-dependent protein kinase-like ER kinase


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha


Peroxisome proliferator-activated receptor gamma coactivator 1-beta


Protein kinase C


Patatin-like phospholipase domain-containing 3


Peroxisome proliferator-activated receptor-δ


Pattern recognition receptor


Regulated on activation, normal T cell expressed and secreted (CCL5)


Receptor-interacting protein


RAR-related orphan receptor A


Reactive oxygen species


SREBP cleavage-activating protein


Short heterodimer partner


Small intestinal bacterial overgrowth


Sterol regulatory element-binding protein-1


Transforming growth factor β-activated kinase 1


Tricarboxylic acid cycle


Toll-like receptor


Transmembrane 6 superfamily member 2


TNF receptor-1


TNF-related apoptosis-inducing ligand


X-box protein-1


Grant Support

R01 DK068450, P30 DK026743.

Conflict of Interest

The author has no conflicts to disclose.


  1. 1.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112(12):1785–8.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013;93(1):1–21. doi: 10.1152/physrev.00017.2012.PubMedCrossRefGoogle Scholar
  4. 4.
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46(11):2347–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Alkhouri N, Gornicka A, Berk MP, Thapaliya S, Dixon LJ, Kashyap S, et al. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem. 2010;285(5):3428–38. doi: 10.1074/jbc.M109.074252.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Gornicka A, Fettig J, Eguchi A, Berk MP, Thapaliya S, Dixon LJ, et al. Adipocyte hypertrophy is associated with lysosomal permeability both in vivo and in vitro: role in adipose tissue inflammation. Am J Physiol Endocrinol Metab. 2012;303(5):E597–606. doi: 10.1152/ajpendo.00022.2012.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389(6651):610–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Cheung AT, Ree D, Kolls JK, Fuselier J, Coy DH, Bryer-Ash M. An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. Endocrinology. 1998;139(12):4928–35. doi: 10.1210/endo.139.12.6336.PubMedGoogle Scholar
  9. 9.
    Takahashi K, Mizuarai S, Araki H, Mashiko S, Ishihara A, Kanatani A, et al. Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J Biol Chem. 2003;278(47):46654–60.PubMedCrossRefGoogle Scholar
  10. 10.
    Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116(6):1494–505.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7(8):947–53. doi: 10.1038/90992.PubMedCrossRefGoogle Scholar
  13. 13.
    Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112(1):91–100. doi: 10.1172/JCI17797112/1/91 [pii].
  14. 14.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    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.Google Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124(1):71–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Cheung O, Kapoor A, Puri P, Sistrun S, Luketic VA, Sargeant CC, et al. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome. Hepatology. 2007;46(4):1091–100.PubMedCrossRefGoogle Scholar
  20. 20.
    van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology. 2009;49(3):791–801.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Ruhl CE, Everhart JE. Trunk fat is associated with increased serum levels of alanine aminotransferase in the United States. Gastroenterology. 2010;138(4):1346–56, 56 e1–3. doi: 10.1053/j.gastro.2009.12.053.
  23. 23.
    Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345–50. doi: 10.1172/JCI15001.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41(4):753–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem. 2000;275(12):8456–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Tilg H, Moschen AR. Role of adiponectin and PBEF/visfatin as regulators of inflammation: involvement in obesity-associated diseases. Clin Sci (Lond). 2008;114(4):275–88.CrossRefGoogle Scholar
  27. 27.
    Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000;105(3):271–8. doi: 10.1172/JCI7901.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Kazantzis M, Stahl A. Fatty acid transport proteins, implications in physiology and disease. Biochim Biophys Acta. 2012;1821(5):852–7. doi: 10.1016/j.bbalip.2011.09.010.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    He J, Lee JH, Febbraio M, Xie W. The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease. Exp Biol Med (Maywood). 2011;236(10):1116–21. doi: 10.1258/ebm.2011.011128.CrossRefGoogle Scholar
  30. 30.
    Mitsuyoshi H, Yasui K, Harano Y, Endo M, Tsuji K, Minami M, et al. Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol Res. 2009;39(4):366–73. doi: 10.1111/j.1872-034X.2008.00464.x.PubMedCrossRefGoogle Scholar
  31. 31.
    Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279(31):32345–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, et al. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest. 2007;117(3):739–45.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7(2):95–6. doi: 10.1016/j.cmet.2007.12.009.PubMedCrossRefGoogle Scholar
  34. 34.
    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 USA. 2010;107(8):3441–6. doi: 10.1073/pnas.0914798107.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118(3):829–38.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146(3):726–35. doi: 10.1053/j.gastro.2013.11.049.PubMedCrossRefGoogle Scholar
  38. 38.
    Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134(2):424–31. doi: 10.1053/j.gastro.2007.11.038.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Ozcan L, Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med. 2012;63:317–28. doi: 10.1146/annurev-med-043010-144749.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010;12 Suppl 2:83–92. doi: 10.1111/j.1463-1326.2010.01275.x.PubMedCrossRefGoogle Scholar
  44. 44.
    Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6(6):1355–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Schuck S, Prinz WA, Thorn KS, Voss C, Walter P. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J Cell Biol. 2009;187(4):525–36. doi: 10.1083/jcb.200907074.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 2004;21(1):81–93. doi: 10.1016/j.immuni.2004.06.010.PubMedCrossRefGoogle Scholar
  47. 47.
    Sriburi R, Jackowski S, Mori K, Brewer JW. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol. 2004;167(1):35–41.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Sriburi R, Bommiasamy H, Buldak GL, Robbins GR, Frank M, Jackowski S, et al. Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis. J Biol Chem. 2007;282(10):7024–34.PubMedCrossRefGoogle Scholar
  49. 49.
    So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, et al. Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 2012;16(4):487–99. doi: 10.1016/j.cmet.2012.09.004.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Wang S, Chen Z, Lam V, Han J, Hassler J, Finck BN, et al. IRE1alpha-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab. 2012;16(4):473–86. doi: 10.1016/j.cmet.2012.09.003.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 2008;320(5882):1492–6.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Singh R, Xiang Y, Wang Y, Baikati K, Cuervo AM, Luu YK, et al. Autophagy regulates adipose mass and differentiation in mice. J Clin Invest. 2009;119(11):3329–39. doi: 10.1172/JCI39228.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, et al. Autophagy regulates lipid metabolism. Nature. 2009;458(7242):1131–5.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Zechner R, Madeo F. Cell biology: another way to get rid of fat. Nature. 2009;458(7242):1118–9. doi: 10.1038/4581118a.PubMedCrossRefGoogle Scholar
  55. 55.
    Fuchs C, Claudel T, Trauner M. Bile acid-mediated control of liver triglycerides. Semin Liver Dis. 2013;33(4):330–42. doi: 10.1055/s-0033-1358520.PubMedCrossRefGoogle Scholar
  56. 56.
    Kong B, Luyendyk JP, Tawfik O, Guo GL. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther. 2009;328(1):116–22. doi: 10.1124/jpet.108.144600.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2010;4(4):741–8. doi: 10.1007/s12072-010-9202-6.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Heni M, Wagner R, Ketterer C, Bohm A, Linder K, Machicao F, et al. Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans. J Clin Endocrinol Metab. 2013;98(7):E1224–9. doi: 10.1210/jc.2013-1177.PubMedCrossRefGoogle Scholar
  59. 59.
    Lu Y, Ma Z, Zhang Z, Xiong X, Wang X, Zhang H, et al. Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. Gut. 2014;63(1):170–8. doi: 10.1136/gutjnl-2012-303150.PubMedCrossRefGoogle Scholar
  60. 60.
    Huerta-Yepez S, Vega M, Garban H, Bonavida B. Involvement of the TNF-alpha autocrine-paracrine loop, via NF-kappaB and YY1, in the regulation of tumor cell resistance to Fas-induced apoptosis. Clin Immunol. 2006;120(3):297–309. doi: 10.1016/j.clim.2006.03.015.PubMedCrossRefGoogle Scholar
  61. 61.
    Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574–82. doi: 10.1053/j.gastro.2013.05.042.PubMedCrossRefGoogle Scholar
  62. 62.
    Kunne C, Acco A, Duijst S, de Waart DR, Paulusma CC, Gaemers I, et al. FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model. Biochim Biophys Acta. 2014;1842(5):739–46. doi: 10.1016/j.bbadis.2014.02.004.PubMedCrossRefGoogle Scholar
  63. 63.
    Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51(4):771–84. doi: 10.1194/jlr.M001602.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65. doi: 10.1016/S0140-6736(14)61933-4.PubMedCrossRefGoogle Scholar
  65. 65.
    Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):645–55. doi: 10.1038/nrgastro.2013.182.PubMedCrossRefGoogle Scholar
  66. 66.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61(1):108–18. doi: 10.1002/hep.27242.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–6. doi: 10.1038/ng.2901.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci USA. 2014;111(24):8913–8. doi: 10.1073/pnas.1323785111.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309. doi: 10.1038/ncomms5309.PubMedCentralPubMedGoogle Scholar
  75. 75.
    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.PubMedCrossRefGoogle Scholar
  76. 76.
    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.
  77. 77.
    Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–31. doi: 10.1038/nature05414.PubMedCrossRefGoogle Scholar
  78. 78.
    Zarrinpar A, Chaix A, Yooseph S, Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 2014;20(6):1006–17. doi: 10.1016/j.cmet.2014.11.008.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Sabate JM, Jouet P, Harnois F, Mechler C, Msika S, Grossin M, et al. High prevalence of small intestinal bacterial overgrowth in patients with morbid obesity: a contributor to severe hepatic steatosis. Obes Surg. 2008;18(4):371–7. doi: 10.1007/s11695-007-9398-2.PubMedCrossRefGoogle Scholar
  80. 80.
    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.PubMedCrossRefGoogle Scholar
  81. 81.
    Yalniz M, Bahcecioglu IH, Ataseven H, Ustundag B, Ilhan F, Poyrazoglu OK, et al. Serum adipokine and ghrelin levels in nonalcoholic steatohepatitis. Mediators Inflamm. 2006;2006(6):34295. doi: 10.1155/MI/2006/34295.PubMedCentralPubMedGoogle Scholar
  82. 82.
    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.PubMedCrossRefGoogle Scholar
  83. 83.
    Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm (Lond). 2010;7:15. doi: 10.1186/1476-9255-7-15.CrossRefGoogle Scholar
  84. 84.
    Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC, et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr. 2008;87(5):1219–23.PubMedGoogle Scholar
  85. 85.
    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.PubMedCrossRefGoogle Scholar
  86. 86.
    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.PubMedCrossRefGoogle Scholar
  87. 87.
    Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci USA. 2006;103(33):12511–6. doi: 10.1073/pnas.0601056103.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Ghoshal AK, Farber E. Choline deficiency, lipotrope deficiency and the development of liver disease including liver cancer: a new perspective. Lab Invest. 1993;68(3):255–60.PubMedGoogle Scholar
  89. 89.
    Vance JE, Vance DE. The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes. Can J Biochem Cell Biol. 1985;63(8):870–81.PubMedCrossRefGoogle Scholar
  90. 90.
    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 USA. 2004;101(44):15718–23. doi: 10.1073/pnas.0407076101.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA. 2007;104(3):979–84.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7(12):691–701. doi: 10.1038/nrgastro.2010.172.PubMedCrossRefGoogle Scholar
  93. 93.
    Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146(6):1513–24. doi: 10.1053/j.gastro.2014.01.020.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. 2014;66(4):948–83. doi: 10.1124/pr.113.008201.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Mayes PA. Intermediary metabolism of fructose. Am J Clin Nutr. 1993;58(5 Suppl):754S–65.PubMedGoogle Scholar
  97. 97.
    Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Okazaki H, Tamura Y, et al. Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice. Diabetes. 2004;53(3):560–9.PubMedCrossRefGoogle Scholar
  98. 98.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Vos MB, Colvin R, Belt P, Molleston JP, Murray KF, Rosenthal P, et al. Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. J Pediatr Gastroenterol Nutr. 2012;54(1):90–6. doi: 10.1097/MPG.0b013e318229da1a.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Le KA, Ith M, Kreis R, Faeh D, Bortolotti M, Tran C, et al. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr. 2009;89(6):1760–5.PubMedCrossRefGoogle Scholar
  102. 102.
    Tappy L, Le KA. Does fructose consumption contribute to non-alcoholic fatty liver disease? Clin Res Hepatol Gastroenterol. 2012;36(6):554–60. doi: 10.1016/j.clinre.2012.06.005.PubMedCrossRefGoogle Scholar
  103. 103.
    Pickens MK, Ogata H, Soon RK, Grenert JP, Maher JJ. Dietary fructose exacerbates hepatocellular injury when incorporated into a methionine-choline-deficient diet. Liver Int. 2010;30(8):1229–39. doi: 10.1111/j.1478-3231.2010.02285.x. LIV2285 [pii].PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G987–95.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Machado RM, Stefano JT, Oliveira CP, Mello ES, Ferreira FD, Nunes VS, et al. Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. J Nutr. 2010;140(6):1127–32. doi: 10.3945/jn.109.117937.PubMedCrossRefGoogle Scholar
  106. 106.
    Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 2010;91(3):502–9. doi: 10.3945/ajcn.2008.26285.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Buettner R, Parhofer KG, Woenckhaus M, Wrede CE, Kunz-Schughart LA, Scholmerich J, et al. Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J Mol Endocrinol. 2006;36(3):485–501. doi: 10.1677/jme.1.01909.PubMedCrossRefGoogle Scholar
  108. 108.
    Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem. 2007;282(4):2483–93.PubMedCrossRefGoogle Scholar
  109. 109.
    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.PubMedCrossRefGoogle Scholar
  110. 110.
    Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson HE, Larsson A, et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes. 2014;63(7):2356–68. doi:10.2337/db13-1622.PubMedCrossRefGoogle Scholar
  111. 111.
    Ioannou GN, Morrow OB, Connole ML, Lee SP. Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population. Hepatology. 2009;50(1):175–84. doi: 10.1002/hep.22941.PubMedCrossRefGoogle Scholar
  112. 112.
    Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology. 2007;46(5):1392–403. doi: 10.1002/hep.21874.PubMedCrossRefGoogle Scholar
  113. 113.
    Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lutjohann D, et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology. 2008;48(2):474–86. doi: 10.1002/hep.22363.PubMedCrossRefGoogle Scholar
  114. 114.
    Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011;301(5):G825–34. doi: 10.1152/ajpgi.00145.2011.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Van Rooyen DM, Larter CZ, Haigh WG, Yeh MM, Ioannou G, Kuver R et al. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology. 2011;141(4):1393–403, 403 e1–5. doi: 10.1053/j.gastro.2011.06.040.
  116. 116.
    Savard C, Tartaglione EV, Kuver R, Haigh WG, Farrell GC, Subramanian S, et al. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. Hepatology. 2013;57(1):81–92. doi: 10.1002/hep.25789.PubMedCrossRefGoogle Scholar
  117. 117.
    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.PubMedCrossRefGoogle Scholar
  118. 118.
    Bass J. Circadian topology of metabolism. Nature. 2012;491(7424):348–56. doi: 10.1038/nature11704.PubMedCrossRefGoogle Scholar
  119. 119.
    Mazzoccoli G, Vinciguerra M, Oben J, Tarquini R, De Cosmo S. Non-alcoholic fatty liver disease: the role of nuclear receptors and circadian rhythmicity. Liver Int. 2014;34(8):1133–52. doi: 10.1111/liv.12534.PubMedCrossRefGoogle Scholar
  120. 120.
    Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012;15(6):848–60. doi: 10.1016/j.cmet.2012.04.019.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014;20(6):991–1005. doi: 10.1016/j.cmet.2014.11.001.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? [editorial]. Gastroenterology. 1998;114(4):842–5.PubMedCrossRefGoogle Scholar
  123. 123.
    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.PubMedCrossRefGoogle Scholar
  124. 124.
    Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125(2):437–43.PubMedCrossRefGoogle Scholar
  125. 125.
    Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol. 2003;39(6):978–83.PubMedCrossRefGoogle Scholar
  126. 126.
    Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA. 2004;101(13):4477–82. doi: 10.1073/pnas.0306068101.PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Zou C, Ma J, Wang X, Guo L, Zhu Z, Stoops J, et al. Lack of Fas antagonism by Met in human fatty liver disease. Nat Med. 2007;13(9):1078–85.PubMedCrossRefGoogle Scholar
  128. 128.
    Kroy DC, Schumacher F, Ramadori P, Hatting M, Bergheim I, Gassler N, et al. Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice. J Hepatol. 2014;61(4):883–90. doi: 10.1016/j.jhep.2014.05.019.PubMedCrossRefGoogle Scholar
  129. 129.
    Sommerfeld A, Reinehr R, Haussinger D. Free fatty acids shift insulin-induced hepatocyte proliferation towards CD95-dependent apoptosis. J Biol Chem. 2014;290(7):4398–409. doi: 10.1074/jbc.M114.617035.PubMedCrossRefGoogle Scholar
  130. 130.
    Reinehr R, Sommerfeld A, Haussinger D. Insulin induces swelling-dependent activation of the epidermal growth factor receptor in rat liver. J Biol Chem. 2010;285(34):25904–12. doi: 10.1074/jbc.M110.125781.PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5(2):157–63. doi: 10.1038/5517.PubMedCrossRefGoogle Scholar
  132. 132.
    Kimberley FC, Screaton GR. Following a TRAIL: update on a ligand and its five receptors. Cell Res. 2004;14(5):359–72. doi: 10.1038/ Scholar
  133. 133.
    Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ. Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut. 2007;56(8):1124–31.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Farrell GC, Larter CZ, Hou JY, Zhang RH, Yeh MM, Williams J, et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J Gastroenterol Hepatol. 2009;24(3):443–52. doi: 10.1111/j.1440-1746.2009.05785.x. JGH5785 [pii].PubMedCrossRefGoogle Scholar
  135. 135.
    Cazanave SC, Mott JL, Bronk SF, Werneburg NW, Fingas CD, Meng XW, et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J Biol Chem. 2011;286(45):39336–48. doi: 10.1074/jbc.M111.280420.PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Idrissova L, Malhi H, Werneburg NW, LeBrasseur NK, Bronk SF, Fingas C, et al. Trail receptor deletion in mice suppresses the inflammation of nutrient excess. J Hepatol. 2015;62(5):1156–63. doi: 10.1016/j.jhep.2014.11.033.PubMedCrossRefGoogle Scholar
  137. 137.
    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.PubMedGoogle Scholar
  138. 138.
    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.PubMedGoogle Scholar
  139. 139.
    Xu Y, Bialik S, Jones BE, Iimuro Y, Kitsis RN, Srinivasan A, et al. NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis. Am J Physiol. 1998;275(4 Pt 1):C1058–66.PubMedGoogle Scholar
  140. 140.
    Inokuchi-Shimizu S, Park EJ, Roh YS, Yang L, Zhang B, Song J, et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest. 2014;124(8):3566–78. doi: 10.1172/JCI74068.PubMedCentralPubMedCrossRefGoogle Scholar
  141. 141.
    Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005;120(5):649–61. doi: 10.1016/j.cell.2004.12.041.PubMedCrossRefGoogle Scholar
  142. 142.
    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.PubMedCrossRefGoogle Scholar
  143. 143.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5(4):a008656. doi: 10.1101/cshperspect.a008656.PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38(2):209–23. doi: 10.1016/j.immuni.2013.02.003.PubMedCrossRefGoogle Scholar
  146. 146.
    Chen X, Li W, Ren J, Huang D, He WT, Song Y, et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 2014;24(1):105–21. doi: 10.1038/cr.2013.171.PubMedCentralPubMedCrossRefGoogle Scholar
  147. 147.
    Cusi K, Chang Z, Harrison S, Lomonaco R, Bril F, Orsak B, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2014;60(1):167–74. doi: 10.1016/j.jhep.2013.07.042.PubMedCrossRefGoogle Scholar
  148. 148.
    Gautheron J, Vucur M, Reisinger F, Cardenas DV, Roderburg C, Koppe C, et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol Med. 2014;6(8):1062–74. doi: 10.15252/emmm.201403856.PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Hatting M, Zhao G, Schumacher F, Sellge G, Al Masaoudi M, Gabetaler N, et al. Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents. Hepatology. 2013;57(6):2189–201. doi: 10.1002/hep.26271.PubMedCrossRefGoogle Scholar
  150. 150.
    Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281(17):12093–101.PubMedCrossRefGoogle Scholar
  151. 151.
    Barreyro FJ, Kobayashi S, Bronk SF, Werneburg NW, Malhi H, Gores GJ. Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis. J Biol Chem. 2007;282(37):27141–54.PubMedCrossRefGoogle Scholar
  152. 152.
    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. doi: 10.1194/jlr.M700184-JLR200.PubMedCrossRefGoogle Scholar
  153. 153.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    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.PubMedCrossRefGoogle Scholar
  155. 155.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  156. 156.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Wei Y, Wang D, Gentile CL, Pagliassotti MJ. Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol Cell Biochem. 2009;331(1-2):31–40. doi: 10.1007/s11010-009-0142-1.PubMedCentralPubMedCrossRefGoogle Scholar
  158. 158.
    Akazawa Y, Cazanave S, Mott JL, Elmi N, Bronk SF, Kohno S, et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J Hepatol. 2010;52(4):586–93. doi: 10.1016/j.jhep.2010.01.003.PubMedCentralPubMedCrossRefGoogle Scholar
  159. 159.
    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.PubMedCrossRefGoogle Scholar
  160. 160.
    Win S, Than TA, Fernandez-Checa JC, Kaplowitz N. JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis. 2014;5, e989. doi: 10.1038/cddis.2013.522.PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Yamamoto K, Ichijo H, Korsmeyer SJ. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol. 1999;19(12):8469–78.PubMedCentralPubMedCrossRefGoogle Scholar
  162. 162.
    Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA. 2003;100(5):2432–7. doi: 10.1073/pnas.0438011100.PubMedCentralPubMedCrossRefGoogle Scholar
  163. 163.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  164. 164.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  165. 165.
    McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21(4):1249–59.PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129(7):1337–49.PubMedCrossRefGoogle Scholar
  167. 167.
    Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998;12(7):982–95.PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ. Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest. 2008;118(10):3378–89.PubMedCentralPubMedCrossRefGoogle Scholar
  169. 169.
    Soon RK, Jr., Yan JS, Grenert JP, Maher JJ. Stress signaling in the methionine-choline-deficient model of murine fatty liver disease. Gastroenterology. 2010;139(5):1730–9, 9 e1. doi: 10.1053/j.gastro.2010.07.046.
  170. 170.
    Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ. Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab. 2010;298(5):E1027–35. doi: 10.1152/ajpendo.00642.2009. ajpendo.00642.2009 [pii].PubMedCentralPubMedCrossRefGoogle Scholar
  171. 171.
    Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18(24):3066–77.PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Cookson BT, Brennan MA. Pro-inflammatory programmed cell death. Trends Microbiol. 2001;9(3):113–4.PubMedCrossRefGoogle Scholar
  173. 173.
    Fink SL, Cookson BT. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol. 2006;8(11):1812–25. doi: 10.1111/j.1462-5822.2006.00751.x.PubMedCrossRefGoogle Scholar
  174. 174.
    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.Google Scholar
  175. 175.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  176. 176.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    Dixon LJ, Berk M, Thapaliya S, Papouchado BG, Feldstein AE. Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab Invest. 2012;92(5):713–23. doi: 10.1038/labinvest.2012.45.PubMedCrossRefGoogle Scholar
  178. 178.
    Guicciardi ME, Malhi H, Mott JL, Gores GJ. Apoptosis and necrosis in the liver. Compr Physiol. 2013;3(2):977–1010. doi: 10.1002/cphy.c120020.PubMedGoogle Scholar
  179. 179.
    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.PubMedCrossRefGoogle Scholar
  180. 180.
    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):846–56, 56 e1–6. doi: 10.1053/j.gastro.2010.05.039.
  181. 181.
    Satapati S, Sunny NE, Kucejova B, Fu X, He TT, Mendez-Lucas A, et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res. 2012;53(6):1080–92. doi: 10.1194/jlr.M023382.PubMedCentralPubMedCrossRefGoogle Scholar
  182. 182.
    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.PubMedCrossRefGoogle Scholar
  183. 183.
    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.PubMedCrossRefGoogle Scholar
  184. 184.
    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.PubMedCrossRefGoogle Scholar
  185. 185.
    Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology. 2014;147(4):765–83. doi: 10.1053/j.gastro.2014.07.018. 4.PubMedCentralPubMedCrossRefGoogle Scholar
  186. 186.
    Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462(2):245–53. doi: 10.1016/ Scholar
  187. 187.
    Amir M, Zhao E, Fontana L, Rosenberg H, Tanaka K, Gao G, et al. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ. 2013;20(7):878–87. doi: 10.1038/cdd.2013.21.PubMedCentralPubMedCrossRefGoogle Scholar
  188. 188.
    Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014;5, e1179. doi: 10.1038/cddis.2014.162.PubMedCentralPubMedCrossRefGoogle Scholar
  189. 189.
    Fucho R, Martinez L, Baulies A, Torres S, Tarrats N, Fernandez A, et al. ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis. J Hepatol. 2014;61(5):1126–34. doi: 10.1016/j.jhep.2014.06.009.PubMedCentralPubMedCrossRefGoogle Scholar
  190. 190.
    Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, et al. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res. 2014;44(9):1026–36. doi: 10.1111/hepr.12282.PubMedCrossRefGoogle Scholar
  191. 191.
    Lin CW, Zhang H, Li M, Xiong X, Chen X, Dong XC, et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol. 2013;58(5):993–9. doi: 10.1016/j.jhep.2013.01.011.PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    Garcia-Ruiz C, Mato JM, Vance D, Kaplowitz N, Fernandez-Checa JC. Acid sphingomyelinase-ceramide system in steatohepatitis: a novel target regulating multiple pathways. J Hepatol. 2015;62(1):219–33. doi: 10.1016/j.jhep.2014.09.023.PubMedCrossRefGoogle Scholar
  193. 193.
    Garcia-Ruiz C, Colell A, Mari M, Morales A, Calvo M, Enrich C, et al. Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest. 2003;111(2):197–208. doi: 10.1172/JCI16010.PubMedCentralPubMedCrossRefGoogle Scholar
  194. 194.
    Ramos B, El Mouedden M, Claro E, Jackowski S. Inhibition of CTP:phosphocholine cytidylyltransferase by C(2)-ceramide and its relationship to apoptosis. Mol Pharmacol. 2002;62(5):1068–75.PubMedCrossRefGoogle Scholar
  195. 195.
    Frago LM, Paneda C, Fabregat I, Varela-Nieto I. Short-chain ceramide regulates hepatic methionine adenosyltransferase expression. J Hepatol. 2001;34(2):192–201.PubMedCrossRefGoogle Scholar
  196. 196.
    Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology. 2007;45(5):1306–12. doi: 10.1002/hep.21650.PubMedCrossRefGoogle Scholar
  197. 197.
    Fan JG, Xu ZJ, Wang GL. Effect of lactulose on establishment of a rat non-alcoholic steatohepatitis model. World J Gastroenterol. 2005;11(32):5053–6.PubMedCentralPubMedCrossRefGoogle Scholar
  198. 198.
    Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol. 2008;48(6):983–92. doi: 10.1016/j.jhep.2008.01.035. S0168-8278(08)00132-3 [pii].PubMedCrossRefGoogle Scholar
  199. 199.
    Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS One. 2013;8(5), e63388. doi: 10.1371/journal.pone.0063388.PubMedCentralPubMedCrossRefGoogle Scholar
  200. 200.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  201. 201.
    L’Homme L, Esser N, Riva L, Scheen A, Paquot N, Piette J, et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res. 2013;54(11):2998–3008. doi: 10.1194/jlr.M037861.PubMedCentralPubMedCrossRefGoogle Scholar
  202. 202.
    Roh YS, Seki E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 2013;28 Suppl 1:38–42. doi: 10.1111/jgh.12019.PubMedCentralPubMedCrossRefGoogle Scholar
  203. 203.
    Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76. doi: 10.1146/annurev.immunol.21.120601.141126.PubMedCrossRefGoogle Scholar
  204. 204.
    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.PubMedCrossRefGoogle Scholar
  205. 205.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  206. 206.
    Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452(7183):103–7.PubMedCrossRefGoogle Scholar
  207. 207.
    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. doi: 10.1053/j.gastro.2010.03.052. S0016-5085(10)00485-3 [pii].PubMedCentralPubMedCrossRefGoogle Scholar
  208. 208.
    Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–72. doi: 10.1053/j.gastro.2012.09.008.PubMedCrossRefGoogle Scholar
  209. 209.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  210. 210.
    Lee JY, Sohn KH, Rhee SH, 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. 2001;276(20):16683–9. doi: 10.1074/jbc.M011695200.PubMedCrossRefGoogle Scholar
  211. 211.
    Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481(7381):278–86. doi: 10.1038/nature10759.PubMedCrossRefGoogle Scholar
  212. 212.
    Kool M, Petrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol. 2008;181(6):3755–9.PubMedCrossRefGoogle Scholar
  213. 213.
    Chen KW, Gross CJ, Sotomayor FV, Stacey KJ, Tschopp J, Sweet MJ, et al. The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge. Cell Rep. 2014;8(2):570–82. doi: 10.1016/j.celrep.2014.06.028.PubMedCrossRefGoogle Scholar
  214. 214.
    Bakele M, Joos M, Burdi S, Allgaier N, Poschel S, Fehrenbacher B, et al. Localization and functionality of the inflammasome in neutrophils. J Biol Chem. 2014;289(8):5320–9. doi: 10.1074/jbc.M113.505636.PubMedCentralPubMedCrossRefGoogle Scholar
  215. 215.
    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.PubMedCrossRefGoogle Scholar
  216. 216.
    Kamari Y, Shaish A, Vax E, Shemesh S, Kandel-Kfir M, Arbel Y, et al. Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J Hepatol. 2011;55(5):1086–94. doi: 10.1016/j.jhep.2011.01.048.PubMedCentralPubMedCrossRefGoogle Scholar
  217. 217.
    Negrin KA, Roth Flach RJ, DiStefano MT, Matevossian A, Friedline RH, Jung D, et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One. 2014;9(9), e107265. doi: 10.1371/journal.pone.0107265.PubMedCentralPubMedCrossRefGoogle Scholar
  218. 218.
    Wree A, McGeough MD, Pena CA, Schlattjan M, Li H, Inzaugarat ME, et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl). 2014;92(10):1069–82. doi: 10.1007/s00109-014-1170-1.CrossRefGoogle Scholar
  219. 219.
    Allam R, Darisipudi MN, Tschopp J, Anders HJ. Histones trigger sterile inflammation by activating the NLRP3 inflammasome. Eur J Immunol. 2013;43(12):3336–42. doi: 10.1002/eji.201243224.PubMedCrossRefGoogle Scholar
  220. 220.
    Huang H, Chen HW, Evankovich J, Yan W, Rosborough BR, Nace GW, et al. Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury. J Immunol. 2013;191(5):2665–79. doi: 10.4049/jimmunol.1202733.PubMedCentralPubMedCrossRefGoogle Scholar
  221. 221.
    Kim S, Joe Y, Jeong SO, Zheng M, Back SH, Park SW, et al. Endoplasmic reticulum stress is sufficient for the induction of IL-1beta production via activation of the NF-kappaB and inflammasome pathways. Innate Immun. 2014;20(8):799–815. doi: 10.1177/1753425913508593.PubMedCrossRefGoogle Scholar
  222. 222.
    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. doi: 10.1053/j.gastro.2010.08.020.PubMedCentralPubMedCrossRefGoogle Scholar
  223. 223.
    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.PubMedCrossRefGoogle Scholar
  224. 224.
    Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kupffer 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.PubMedCentralPubMedCrossRefGoogle Scholar
  225. 225.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  226. 226.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95. doi: 10.1172/JCI59643.PubMedCentralPubMedCrossRefGoogle Scholar
  227. 227.
    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;59(1):130–42. doi: 10.1002/hep.26607.PubMedCrossRefGoogle Scholar
  228. 228.
    Wan J, Benkdane M, Alons E, Lotersztajn S, Pavoine C. M2 kupffer cells promote hepatocyte senescence: an IL-6-dependent protective mechanism against alcoholic liver disease. Am J Pathol. 2014;184(6):1763–72. doi: 10.1016/j.ajpath.2014.02.014.PubMedCrossRefGoogle Scholar
  229. 229.
    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.CrossRefGoogle Scholar
  230. 230.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  231. 231.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  232. 232.
    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.PubMedCrossRefGoogle Scholar
  233. 233.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  234. 234.
    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.PubMedCrossRefGoogle Scholar
  235. 235.
    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.PubMedCrossRefGoogle Scholar
  236. 236.
    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.PubMedCrossRefGoogle Scholar
  237. 237.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  238. 238.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  239. 239.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  240. 240.
    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.PubMedCrossRefGoogle Scholar
  241. 241.
    Kakisaka K, Cazanave SC, Werneburg NW, Razumilava N, Mertens JC, Bronk SF, et al. A hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes. J Hepatol. 2012;57(4):844–51. doi: 10.1016/j.jhep.2012.05.011.PubMedCentralPubMedCrossRefGoogle Scholar
  242. 242.
    Rangwala F, Guy CD, Lu J, Suzuki A, Burchette JL, Abdelmalek MF, et al. Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol. 2011;224(3):401–10. doi: 10.1002/path.2888.PubMedCentralPubMedCrossRefGoogle Scholar
  243. 243.
    Guy CD, Suzuki A, Zdanowicz M, Abdelmalek MF, Burchette J, Unalp A, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55(6):1711–21. doi: 10.1002/hep.25559.PubMedCentralPubMedCrossRefGoogle Scholar
  244. 244.
    Choi SS, Omenetti A, Syn WK, Diehl AM. The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol. 2011;43(2):238–44. doi: 10.1016/j.biocel.2010.10.015.PubMedCentralPubMedCrossRefGoogle Scholar
  245. 245.
    Syn WK, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 2011;53(1):106–15. doi: 10.1002/hep.23998.PubMedCentralPubMedCrossRefGoogle Scholar
  246. 246.
    Hirsova P, Ibrahim SH, Bronk SF, Yagita H, Gores GJ. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis. PLoS One. 2013;8(7), e70599. doi: 10.1371/journal.pone.0070599.PubMedCentralPubMedCrossRefGoogle Scholar
  247. 247.
    Hirsova P, Gores GJ. Ballooned hepatocytes, undead cells, sonic hedgehog, and Vitamin E: therapeutic implications for nonalcoholic steatohepatitis. Hepatology. 2015;61(1):15–7. doi: 10.1002/hep.27279.PubMedPubMedCentralCrossRefGoogle Scholar
  248. 248.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  249. 249.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  250. 250.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  251. 251.
    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.PubMedGoogle Scholar
  252. 252.
    Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10(11):656–65. doi: 10.1038/nrgastro.2013.183.PubMedCrossRefGoogle Scholar
  253. 253.
    Wunderlich FT, Luedde T, Singer S, Schmidt-Supprian M, Baumgartl J, Schirmacher P, et al. Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA. 2008;105(4):1297–302. doi: 10.1073/pnas.0707849104.PubMedCentralPubMedCrossRefGoogle Scholar
  254. 254.
    Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer. 2009;124(3):540–6. doi: 10.1002/ijc.23995.PubMedCentralPubMedCrossRefGoogle Scholar
  255. 255.
    Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208. doi: 10.1016/j.cell.2009.12.052.PubMedCentralPubMedCrossRefGoogle Scholar
  256. 256.
    Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2007;11(2):119–32. doi: 10.1016/j.ccr.2006.12.016.PubMedCrossRefGoogle Scholar
  257. 257.
    Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C, Farkas T, Lopez-Rivas A, et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 2009;28(6):677–85. doi: 10.1038/emboj.2009.8.PubMedCentralPubMedCrossRefGoogle Scholar
  258. 258.
    Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26(3):331–43. doi: 10.1016/j.ccr.2014.07.001.PubMedCentralPubMedCrossRefGoogle Scholar
  259. 259.
    Sakaki K, Kaufman RJ. Regulation of ER stress-induced macroautophagy by protein kinase C. Autophagy. 2008;4(6):841–3.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of MedicineUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Liver CenterUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.Liver Center LaboratoryUCSF/San Francisco General HospitalSan FranciscoUSA

Personalised recommendations