Skip to main content
SpringerLink
Log in

Nonalcoholic Fatty Liver Disease

  • Chapter
  • First Online:
Book cover Liver Immunology

  • 2518 Accesses

Abstract

Nonalcoholic fatty liver disease (NAFLD) is defined by fat deposition in the liver in the absence of secondary causes for steatosis. The disease spectrum of NAFLD varies from simple steatosis, through steatosis with inflammation with or without hepatocyte injury, to cirrhosis at the other end of the spectrum [1]. Nonalcoholic steatohepatitis (NASH) is a part of NAFLD spectrum and is characterized by the presence of hepatic fat deposition, inflammation, and most importantly hepatocyte damage in the form of characteristic ballooning injury. Current AASLD consensus guidelines require the presence of liver injury in the form of ballooning to distinguish NASH from other disorders of the NAFLD disease spectrum. On the other hand, the term nonalcoholic fatty liver (NAFL) is classically used to describe steatosis in the absence of ballooning [2–4]. The histological criterion for diagnosing NAFLD is fat infiltration in more than 5 % of the hepatocytes. The accumulation of fat usually starts in zone 3 that is the peri-sinusoidal region. Although hepatic steatosis or inflammation in itself does not define NASH, both have been associated with liver-related mortality. Steatosis has been linked to increased cardiovascular mortality [4]. Some studies have determined that inflammation that extends beyond the portal tracks has been correlated with advanced fibrosis, while others have not found this relation. Similarly, evidence suggests that pan-acinar steatosis is predictive of fibrosis [5, 6]. Age and degree of inflammation on biopsy performed at diagnosis have been correlated to progression of fibrosis in a systematic review of several clinical trials. Of the several histological systems proposed for NAFLD diagnosis, those incorporating fibrosis are predictive of long-term mortality. Fibrosis is the only histological feature that is individually related to prognosis [5–8]. On the other hand, clinical presence of obesity and type 2 diabetes has been associated with disease progression [1, 9]. Outcomes of advanced NAFLD (Child-Pugh B and C) have prognosis comparable to those with similar stage of hepatitis C-related liver disease [10, 11].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.

    PubMed  Google Scholar 

  2. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.

    PubMed  Google Scholar 

  3. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, Tordjman J, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–9.

    PubMed  Google Scholar 

  4. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TI, Becker U, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–5.

    PubMed  CAS  Google Scholar 

  5. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, Network NCR. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–20.

    PubMed  CAS  Google Scholar 

  6. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  8. Angulo P. Diagnosing steatohepatitis and predicting liver-related mortality in patients with NAFLD: two distinct concepts. Hepatology. 2011;53:1792–4.

    PubMed  Google Scholar 

  9. Larter CZ, Chitturi S, Heydet D, Farrell GC. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol. 2010;25:672–90.

    PubMed  CAS  Google Scholar 

  10. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, Adams LA, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54:1208–16.

    PubMed  Google Scholar 

  11. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–7.

    PubMed  Google Scholar 

  12. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–85.

    PubMed  CAS  Google Scholar 

  13. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124–31.

    PubMed  Google Scholar 

  14. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:511–31.

    PubMed  Google Scholar 

  15. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.

    PubMed  Google Scholar 

  16. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42:44–52.

    PubMed  Google Scholar 

  17. Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–60.

    PubMed  Google Scholar 

  18. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–49.

    PubMed  Google Scholar 

  19. Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, Hultcrantz R. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.

    PubMed  Google Scholar 

  20. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.

    PubMed  Google Scholar 

  21. Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007;46:1081–90.

    PubMed  CAS  Google Scholar 

  22. Monetti M, Levin MC, Watt MJ, Hubbard BK, Newgard C, Farese RV, Sr., Hevener AL, et al. Hepatic acyl-CoA:diacylglycerol acyltransferase (DGAT) overexpression, diacylglycerol, and insulin sensitivity. Proc Natl Acad Sci U S A. 2011;108:E523; author reply E524.

    Google Scholar 

  23. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–74.

    PubMed  CAS  Google Scholar 

  24. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007;6:69–78.

    PubMed  CAS  Google Scholar 

  25. McClain CJ, Barve S, Deaciuc I. Good fat/bad fat. Hepatology. 2007;45:1343–6.

    PubMed  CAS  Google Scholar 

  26. Nolan CJ, Larter CZ. Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it? J Gastroenterol Hepatol. 2009;24:703–6.

    PubMed  CAS  Google Scholar 

  27. Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:360–9.

    PubMed  CAS  Google Scholar 

  28. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab. 2006;291:E275–81.

    PubMed  CAS  Google Scholar 

  29. 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;115:1343–51.

    PubMed  CAS  Google Scholar 

  30. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–50.

    PubMed  CAS  Google Scholar 

  31. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–92.

    PubMed  CAS  Google Scholar 

  32. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–10.

    PubMed  CAS  Google Scholar 

  33. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–23.

    PubMed  CAS  Google Scholar 

  34. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–13.

    PubMed  CAS  Google Scholar 

  35. Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, Torimura T, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27:103–7.

    PubMed  CAS  Google Scholar 

  36. Suzuki A, Lindor K, St Saver J, Lymp J, Mendes F, Muto A, Okada T, et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol. 2005;43:1060–6.

    PubMed  CAS  Google Scholar 

  37. Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, Karim R, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9.

    PubMed  CAS  Google Scholar 

  38. Park SH, Kim BI, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, et al. Body fat distribution and insulin resistance: beyond obesity in nonalcoholic fatty liver disease among overweight men. J Am Coll Nutr. 2007;26:321–6.

    PubMed  Google Scholar 

  39. Thomas EL, Hamilton G, Patel N, O’Dwyer R, Dore CJ, Goldin RD, Bell JD, et al. Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. Gut. 2005;54:122–7.

    PubMed  CAS  Google Scholar 

  40. Cheung O, Kapoor A, Puri P, Sistrun S, Luketic VA, Sargeant CC, Contos MJ, et al. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome. Hepatology. 2007;46:1091–100.

    PubMed  Google Scholar 

  41. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987–1000.

    PubMed  CAS  Google Scholar 

  42. Svegliati-Baroni G, Ridolfi F, Di Sario A, Casini A, Marucci L, Gaggiotti G, Orlandoni P, et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology. 1999;29:1743–51.

    PubMed  CAS  Google Scholar 

  43. Choudhury J, Sanyal AJ. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:575–94, ix.

    Google Scholar 

  44. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, et al. The nuclear receptor LXR is a glucose sensor. Nature. 2007;445:219–23.

    PubMed  CAS  Google Scholar 

  45. Larter CZ, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH: which is the best target to treat? J Hepatol. 2006;44:253–61.

    PubMed  Google Scholar 

  46. Edvardsson U, Bergstrom M, Alexandersson M, Bamberg K, Ljung B, Dahllof B. Rosiglitazone (BRL49653), a PPARgamma-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. J Lipid Res. 1999;40:1177–84.

    PubMed  CAS  Google Scholar 

  47. Chao L, Marcus-Samuels B, Mason MM, Moitra J, Vinson C, Arioglu E, Gavrilova O, et al. Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest. 2000;106:1221–8.

    PubMed  CAS  Google Scholar 

  48. Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer Jr B, et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest. 2003;111:737–47.

    PubMed  CAS  Google Scholar 

  49. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79:1147–56.

    PubMed  CAS  Google Scholar 

  50. Semple RK, Chatterjee VK, O’Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest. 2006;116:581–9.

    PubMed  CAS  Google Scholar 

  51. Pfutzner A, Hohberg C, Lubben G, Pahler S, Pfutzner AH, Kann P, Forst T. Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Horm Metab Res. 2005;37:510–5.

    PubMed  CAS  Google Scholar 

  52. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–61.

    PubMed  Google Scholar 

  53. Larter CZ, Yeh MM, Van Rooyen DM, Teoh NC, Brooling J, Hou JY, Williams J, et al. Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. J Gastroenterol Hepatol. 2009;24:1658–68.

    PubMed  CAS  Google Scholar 

  54. Larter CZ, Yeh MM. Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol. 2008;23:1635–48.

    PubMed  Google Scholar 

  55. Van Rooyen DM, Larter CZ, Haigh WG, Yeh MM, Ioannou G, Kuver R, Lee SP, et al. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology. 2011;141:1393–403, 1403.e1391–5.

    Google Scholar 

  56. Lo L, McLennan SV, Williams PF, Bonner J, Chowdhury S, McCaughan GW, Gorrell MD, et al. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol. 2011;55:435–44.

    PubMed  CAS  Google Scholar 

  57. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol. 2006;87:1–16.

    PubMed  CAS  Google Scholar 

  58. 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:G987–95.

    PubMed  CAS  Google Scholar 

  59. Toshimitsu K, Matsuura B, Ohkubo I, Niiya T, Furukawa S, Hiasa Y, Kawamura M, et al. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition. 2007;23:46–52.

    PubMed  Google Scholar 

  60. Kechagias S, Ernersson A, Dahlqvist O, Lundberg P, Lindstrom T, Nystrom FH, Fast Food Study Group. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008;57:649–54.

    PubMed  CAS  Google Scholar 

  61. Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol. 2001;96:2957–61.

    PubMed  CAS  Google Scholar 

  62. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, Shiehmorteza M, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136:1585–92.

    PubMed  Google Scholar 

  63. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5.

    PubMed  CAS  Google Scholar 

  64. Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, Leathart JB, et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut. 2010;59:267–73.

    PubMed  CAS  Google Scholar 

  65. Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH. Hepatology. 2008;47:1167–77.

    PubMed  CAS  Google Scholar 

  66. Gonzalez-Sanchez JL, Zabena CA, Martinez-Larrad MT, Fernandez-Perez C, Perez-Barba M, Laakso M, Serrano-Rios M. An SNP in the adiponectin gene is associated with decreased serum adiponectin levels and risk for impaired glucose tolerance. Obes Res. 2005;13:807–12.

    PubMed  CAS  Google Scholar 

  67. Demirag MD, Onen HI, Karaoguz MY, Dogan I, Karakan T, Ekmekci A, Guz G. Apolipoprotein E gene polymorphism in nonalcoholic fatty liver disease. Dig Dis Sci. 2007;52:3399–403.

    PubMed  CAS  Google Scholar 

  68. Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology. 2011;53:467–74.

    PubMed  CAS  Google Scholar 

  69. Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M, Akisawa N, et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol. 2004;40:781–6.

    PubMed  CAS  Google Scholar 

  70. Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. Gastroenterol Hepatol. 2012;35:32–41.

    PubMed  Google Scholar 

  71. Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology. 1998;27:128–33.

    PubMed  CAS  Google Scholar 

  72. Chalasani N, Gorski JC, Asghar MS, Asghar A, Foresman B, Hall SD, Crabb DW. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology. 2003;37:544–50.

    PubMed  CAS  Google Scholar 

  73. Gornicka A, Morris-Stiff G, Thapaliya S, Papouchado BG, Berk M, Feldstein AE. Transcriptional profile of genes involved in oxidative stress and antioxidant defense in a dietary murine model of steatohepatitis. Antioxid Redox Signal. 2011;15:437–45.

    PubMed  CAS  Google Scholar 

  74. Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin Chim Acta. 2011;412:1297–305.

    PubMed  CAS  Google Scholar 

  75. George J, Pera N, Phung N, Leclercq I, Yun Hou J, Farrell G. Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis. J Hepatol. 2003;39:756–64.

    PubMed  CAS  Google Scholar 

  76. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

    PubMed  CAS  Google Scholar 

  77. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem. 2005;74:739–89.

    PubMed  Google Scholar 

  78. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology. 2011;53:1752–63.

    PubMed  CAS  Google Scholar 

  79. Rahman SM, Schroeder-Gloeckler JM, Janssen RC, Jiang H, Qadri I, Maclean KN, Friedman JE. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology. 2007;45:1108–17.

    PubMed  CAS  Google Scholar 

  80. Rinella ME, Siddiqui MS, Gardikiotes K, Gottstein J, Elias M, Green RM. Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis. Hepatology. 2011;54:1600–9.

    PubMed  CAS  Google Scholar 

  81. Leclercq IA, Van Rooyen DM, Farrell GC. Hepatic endoplasmic reticulum stress in obesity: deeper insights into processes, but are they relevant to nonalcoholic steatohepatitis? Hepatology. 2011;54:2260–5.

    PubMed  Google Scholar 

  82. Adams LA, Angulo P, Petz J, Keach J, Lindor KD. A pilot trial of high-dose ursodeoxycholic acid in nonalcoholic steatohepatitis. Hepatol Int. 2010;4:628–33.

    PubMed  Google Scholar 

  83. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, Zeuzem S, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472–9.

    PubMed  CAS  Google Scholar 

  84. Pessayre D. Role of mitochondria in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2007;22 Suppl 1:S20–7.

    PubMed  CAS  Google Scholar 

  85. Rashid A, Wu TC, Huang CC, Chen CH, Lin HZ, Yang SQ, Lee FY, et al. Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver. Hepatology. 1999;29:1131–8.

    PubMed  CAS  Google Scholar 

  86. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333:1109–12.

    PubMed  CAS  Google Scholar 

  87. van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48:449–57.

    PubMed  Google Scholar 

  88. Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue—an update. Horm Metab Res. 2007;39:314–21.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  90. Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun. 2004;323:630–5.

    PubMed  CAS  Google Scholar 

  91. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005;54:117–21.

    PubMed  CAS  Google Scholar 

  92. Gelsinger C, Tschoner A, Kaser S, Ebenbichler CF. Adipokine update—new molecules, new functions. Wien Med Wochenschr. 2010;160:377–90.

    PubMed  Google Scholar 

  93. Mantzoros CS. The role of leptin and hypothalamic neuropeptides in energy homeostasis: update on leptin in obesity. Growth Horm IGF Res. 2001;11(Suppl A):S85–9.

    PubMed  Google Scholar 

  94. Meier CA. Leptin secretion and action: an update. Eur J Endocrinol. 1996;134:543–5.

    PubMed  CAS  Google Scholar 

  95. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007;104:13780–5.

    PubMed  CAS  Google Scholar 

  96. Tennyson CA, Friedman G. Microecology, obesity, and probiotics. Curr Opin Endocrinol Diabetes Obes. 2008;15:422–7.

    PubMed  Google Scholar 

  97. DiBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc. 2008;83:460–9.

    PubMed  Google Scholar 

  98. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718–23.

    PubMed  Google Scholar 

  99. Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G, Martines D. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G518–25.

    PubMed  CAS  Google Scholar 

  100. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–11.

    PubMed  CAS  Google Scholar 

  101. Nair S, Cope K, Risby TH, Diehl AM. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:1200–4.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  103. Salaspuro M. Bacteriocolonic pathway for ethanol oxidation: characteristics and implications. Ann Med. 1996;28:195–200.

    PubMed  CAS  Google Scholar 

  104. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37:343–50.

    PubMed  CAS  Google Scholar 

  105. Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C, Del Vecchio BC. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39:540–3.

    PubMed  Google Scholar 

  106. Stanton MC, Chen SC, Jackson JV, Rojas-Triana A, Kinsley D, Cui L, Fine JS, et al. Inflammatory signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J Inflamm (Lond). 2011;8:8.

    CAS  Google Scholar 

  107. 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;25:4301–11.

    PubMed  CAS  Google Scholar 

  108. Neels JG, Olefsky JM. Inflamed fat: what starts the fire? J Clin Invest. 2006;116:33–5.

    PubMed  CAS  Google Scholar 

  109. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.

    PubMed  CAS  Google Scholar 

  110. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.

    PubMed  CAS  Google Scholar 

  111. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007;56:16–23.

    PubMed  CAS  Google Scholar 

  112. 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;47:571–9.

    PubMed  CAS  Google Scholar 

  113. Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol. 2009;51:212–23.

    PubMed  CAS  Google Scholar 

  114. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110:1564–71.

    PubMed  CAS  Google Scholar 

  115. Park JW, Jeong G, Kim SJ, Kim MK, Park SM. Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J Gastroenterol Hepatol. 2007;22:491–7.

    PubMed  CAS  Google Scholar 

  116. Tonan T, Fujimoto K, Qayyum A, Azuma S, Ishibashi M, Ueno T, Ono N, et al. Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin. Exp Ther Med. 2011;2:607–13.

    PubMed  Google Scholar 

  117. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–35.

    PubMed  CAS  Google Scholar 

  118. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–45.

    PubMed  CAS  Google Scholar 

  119. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.

    PubMed  CAS  Google Scholar 

  120. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology. 2006;44:287–98.

    PubMed  CAS  Google Scholar 

  121. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.

    PubMed  Google Scholar 

  122. Kagan JC, Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell. 2006;125:943–55.

    PubMed  CAS  Google Scholar 

  123. Fitzgerald KA, Chen ZJ. Sorting out Toll signals. Cell. 2006;125:834–6.

    PubMed  CAS  Google Scholar 

  124. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, et al. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem. 2003;278:37041–51.

    PubMed  CAS  Google Scholar 

  125. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–25.

    PubMed  CAS  Google Scholar 

  126. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araujo EP, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007;56:1986–98.

    PubMed  CAS  Google Scholar 

  127. De Nardo D, De Nardo CM, Nguyen T, Hamilton JA, Scholz GM. Signaling crosstalk during sequential TLR4 and TLR9 activation amplifies the inflammatory response of mouse macrophages. J Immunol. 2009;183:8110–8.

    PubMed  Google Scholar 

  128. Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, Olefsky JM, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139:323–34.e327.

    Google Scholar 

  129. Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, Lee WH, et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004;279:16971–9.

    PubMed  CAS  Google Scholar 

  130. Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.

    PubMed  CAS  Google Scholar 

  131. Schneider M, Zimmermann AG, Roberts RA, Zhang L, Swanson KV, Wen H, Davis BK, et al. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappaB. Nat Immunol. 2012;13:823–31.

    PubMed  CAS  Google Scholar 

  132. 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;54:133–44.

    PubMed  CAS  Google Scholar 

  133. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–85.

    PubMed  CAS  Google Scholar 

  134. Bugianesi E, Marchesini G, Gentilcore E, Cua IH, Vanni E, Rizzetto M, George J. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis. Hepatology. 2006;44:1648–55.

    PubMed  CAS  Google Scholar 

  135. Taniguchi CM, Ueki K, Kahn R. Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest. 2005;115:718–27.

    PubMed  CAS  Google Scholar 

  136. Ueki K, Kondo T, Tseng YH, Kahn CR. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A. 2004;101:10422–7.

    PubMed  CAS  Google Scholar 

  137. Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006;43:163–72.

    PubMed  CAS  Google Scholar 

  138. Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes. 2005;54 Suppl 2:S73–8.

    PubMed  CAS  Google Scholar 

  139. Perseghin G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S6–11.

    PubMed  CAS  Google Scholar 

  140. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.

    PubMed  CAS  Google Scholar 

  141. Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093–101.

    PubMed  CAS  Google Scholar 

  142. Pirola L, Johnston AM, Van Obberghen E. Modulation of insulin action. Diabetologia. 2004;47:170–84.

    PubMed  CAS  Google Scholar 

  143. Pirola L, Johnston AM, Van Obberghen E. Modulators of insulin action and their role in insulin resistance. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S61–4.

    PubMed  CAS  Google Scholar 

  144. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934–45.

    PubMed  CAS  Google Scholar 

  145. Lin RS, Lee FY, Lee SD, Tsai YT, Lin HC, Lu RH, Hsu WC, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol. 1995;22:165–72.

    PubMed  CAS  Google Scholar 

  146. Aoyama T, Paik YH, Seki E. Toll-like receptor signaling and liver fibrosis. Gastroenterol Res Pract. 2010;2010:1-8.

    Google Scholar 

  147. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:1324–32.

    PubMed  CAS  Google Scholar 

  148. Perugorria MJ, Murphy LB, Fullard N, Chakraborty JB, Virla D, Wilson CL, Oakley F, et al. Tpl2/Cot is required for activation of ERK in liver injury and TLR induced TIMP-1 gene transcription in hepatic stellate cells. Hepatology. 2013;57:1238–49.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work has been supported by the NIH T32 Training Grant

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Hepatology & Nutrition, Virginia Commonwealth University, Richmond, VA, 23298-0341, USA

    Vaishali Patel M.B.B.S & Arun J. Sanyal M.B.B.S., M.D.

  2. Center for Clinical and Translational Research, Richmond, VA, 23298-0341, USA

    Vaishali Patel M.B.B.S & Arun J. Sanyal M.B.B.S., M.D.

Authors
  1. Vaishali Patel M.B.B.S
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arun J. Sanyal M.B.B.S., M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arun J. Sanyal M.B.B.S., M.D. .

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, California, USA

    M. Eric Gershwin

  2. Medicine and Surgery, Baylor College of Medicine, Houston, Texas, USA

    John M. Vierling

  3. Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Germany

    Michael P. Manns

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Patel, V., Sanyal, A.J. (2014). Nonalcoholic Fatty Liver Disease. In: Gershwin, M., Vierling, J., Manns, M. (eds) Liver Immunology. Springer, Cham. https://doi.org/10.1007/978-3-319-02096-9_23

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-02096-9_23

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-02095-2

  • Online ISBN: 978-3-319-02096-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation