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Animal Models for Nonalcoholic Fatty Liver Disease

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Integrative Weight Management

Part of the book series: Nutrition and Health ((NH))

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by excessive fat accumulation in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, may progress to liver cirrhosis and hepatocellular carcinoma. NAFLD/NASH is considered a hepatic manifestation of metabolic syndrome and is increasing globally with the increased prevalence of obesity. Animal models of NAFLD/NASH yield important information for elucidating the pathogenesis of NAFLD/NASH and for developing new treatments for the disease. An ideal animal model of NAFLD/NASH should correctly reflect both the histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are classified into genetic models, nutritional models, and combination models of genetic and nutritional factors. In this chapter, we review representative animal models of NAFLD/NASH, referring to their advantages and disadvantages.

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Abbreviations

ALT:

Alanine aminotransferase

HF:

High fat

IL:

Interleukin

MCD:

Methionine and choline deficient

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

PTEN:

Phosphatase and tensin homologue deleted on chromosome 10

VLDL:

Very low-density lipoprotein

References

  1. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80.

    Article  PubMed  Google Scholar 

  2. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332:1519–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.

    Article  PubMed  Google Scholar 

  4. Machado M, Cortez-Pinto H. Non-alcoholic steatohepatitis and metabolic syndrome. Curr Opin Clin Nutr Metab Care. 2006;9:637–42.

    Article  PubMed  Google Scholar 

  5. Neuschwander-Tetri BA. Nonalcoholic steatohepatitis and the metabolic syndrome. Am J Med Sci. 2005;330:326–35.

    Article  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Bray GA, York DA. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev. 1979;59:719–809.

    CAS  PubMed  Google Scholar 

  8. Almonacid-Urrego CC, Sanchez-Campos S, Tunon MJ, Gonzalez-Gallego J. Non-alcoholic steatohepatitis: what can we learn from animal models? Curr Med Chem. 2012;19:1389–404.

    Article  CAS  PubMed  Google Scholar 

  9. Diehl AM. Lessons from animal models of NASH. Hepatol Res. 2005;33:138–44.

    Article  CAS  PubMed  Google Scholar 

  10. Fan JG, Qiao L. Commonly used animal models of non-alcoholic steatohepatitis. Hepatobiliary Pancreat Dis Int. 2009;8:233–40.

    PubMed  Google Scholar 

  11. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A. 1997;94:2557–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Leclercq IA, Farrell GC, Schriemer R, Robertson GR. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol. 2002;37:206–13.

    Article  CAS  PubMed  Google Scholar 

  13. Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, Sato N. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34:288–97.

    Article  CAS  PubMed  Google Scholar 

  14. Chalasani N, Crabb DW, Cummings OW, Kwo PY, Asghar A, Pandya PK, Considine RV. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol. 2003;98:2771–6.

    Article  CAS  PubMed  Google Scholar 

  15. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84:491–5.

    Article  CAS  PubMed  Google Scholar 

  16. Wortham M, He L, Gyamfi M, Copple BL, Wan YJ. The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. Dig Dis Sci. 2008;53:2761–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, Whitington PF. Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1035–43.

    Article  CAS  PubMed  Google Scholar 

  18. Schattenberg JM, Galle PR. Animal models of non-alcoholic steatohepatitis: of mice and man. Dig Dis. 2010;28:247–54.

    Article  CAS  PubMed  Google Scholar 

  19. Yang ZH, Miyahara H, Hatanaka A. Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay mice with genetic type 2 diabetes. Lipids Health Dis. 2011;10:120.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Nagarajan P, Mahesh Kumar MJ, Venkatesan R, Majundar SS, Juyal RC. Genetically modified mouse models for the study of nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18:1141–53.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Okumura K, Ikejima K, Kon K, Abe W, Yamashina S, Enomoto N, Takei Y, Sato N. Exacerbation of dietary steatohepatitis and fibrosis in obese, diabetic KK-A(y) mice. Hepatol Res. 2006;36:217–28.

    Article  CAS  PubMed  Google Scholar 

  22. Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, Yoshimatsu H. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004;40:177–84.

    Article  CAS  PubMed  Google Scholar 

  23. Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, Sherwin R, Devaskar S, Lesche R, Magnuson MA, Wu H. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity. Proc Natl Acad Sci U S A. 2004;101:2082–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Sato W, Horie Y, Kataoka E, Ohshima S, Dohmen T, Iizuka M, Sasaki J, Sasaki T, Hamada K, Kishimoto H, Suzuki A, Watanabe S. Hepatic gene expression in hepatocyte-specific Pten deficient mice showing steatohepatitis without ethanol challenge. Hepatol Res. 2006;34:256–65.

    Article  CAS  PubMed  Google Scholar 

  25. Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113:1774–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Yao ZM, Vance DE. Reduction in VLDL, but not HDL, in plasma of rats deficient in choline. Biochem Cell Biol. 1990;68:552–8.

    Article  CAS  PubMed  Google Scholar 

  27. Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest. 2000;105:1067–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Larter CZ, Yeh MM, Williams J, Bell-Anderson KS, Farrell GC. MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. J Hepatol. 2008;49:407–16.

    Article  CAS  PubMed  Google Scholar 

  29. Dela Pena A, Leclercq I, Field J, George J, Jones B, Farrell G. NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology. 2005;129:1663–74.

    Article  CAS  PubMed  Google Scholar 

  30. Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPAR alpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology. 2004;39:1286–96.

    Article  CAS  PubMed  Google Scholar 

  31. Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol. 2004;40:47–51.

    Article  CAS  PubMed  Google Scholar 

  32. Leclercq IA, Lebrun VA, Starkel P, Horsmans YJ. Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPAR gamma agonist pioglitazone. Lab Invest. 2007;87:56–65.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  34. Hebbard L, George J. Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2011;8:34–44.

    Article  CAS  Google Scholar 

  35. Takahashi Y, Soejima Y, Fukusato T. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18:2300–8.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Lieber CS, Leo MA, Mak KM, Xu Y, Cao Q, Ren C, Ponomarenko A, DeCarli LM. Model of nonalcoholic steatohepatitis. Am J Clin Nutr. 2004;79:502–9.

    CAS  PubMed  Google Scholar 

  37. Zou Y, Li J, Lu C, Wang J, Ge J, Huang Y, Zhang L, Wang Y. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sci. 2006;79:1100–7.

    Article  CAS  PubMed  Google Scholar 

  38. Ito M, Suzuki J, Tsujioka S, Sasaki M, Gomori A, Shirakura T, Hirose H, Ito M, Ishihara A, Iwaasa H, Kanatani A. Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. Hepatol Res. 2007;37:50–7.

    Article  CAS  PubMed  Google Scholar 

  39. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H, Gores G. 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:G825–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Deng QG, She H, Cheng JH, French SW, Koop DR, Xiong S, Tsukamoto H. Steatohepatitis induced by intragastric overfeeding in mice. Hepatology. 2005;42:905–14.

    Article  CAS  PubMed  Google Scholar 

  41. Ogasawara M, Hirose A, Ono M, Aritake K, Nozaki Y, Takahashi M, Okamoto N, Sakamoto S, Iwasaki S, Asanuma T, Taniguchi T, Urade Y, Onishi S, Saibara T, Oben JA. A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet. Liver Int. 2011;31:542–51.

    Article  CAS  PubMed  Google Scholar 

  42. Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, Yokoyama M, Honda M, Zen Y, Nakanuma Y, Miyamoto K, Kaneko S. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology. 2007;46:1392–403.

    Article  CAS  PubMed  Google Scholar 

  43. Bhathena J, Kulamarva A, Martoni C, Urbanska AM, Malhotra M, Paul A, Prakash S. Diet-induced metabolic hamster model of nonalcoholic fatty liver disease. Diabetes Metab Syndr Obes. 2011;4:195–203.

    PubMed Central  PubMed  Google Scholar 

  44. Kitamori K, Naito H, Tamada H, Kobayashi M, Miyazawa D, Yasui Y, Sonoda K, Tsuchikura S, Yasui N, Ikeda K, Moriya T, Yamori Y, Nakajima T. Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr. Environ Health Prev Med. 2012;17:173–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Kawasaki T, Igarashi K, Koeda T, Sugimoto K, Nakagawa K, Hayashi S, Yamaji R, Inui H, Fukusato T, Yamanouchi T. Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. J Nutr. 2009;139:2067–71.

    Article  CAS  PubMed  Google Scholar 

  46. Ackerman Z, Oron-Herman M, Grozovski M, Rosenthal T, Pappo O, Link G, Sela BA. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension. 2005;45:1012–8.

    Article  CAS  PubMed  Google Scholar 

  47. Armutcu F, Coskun O, Gurel A, Kanter M, Can M, Ucar F, Unalacak M. Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats. Clin Biochem. 2005;38:540–7.

    Article  CAS  PubMed  Google Scholar 

  48. Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009;50:1094–104.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Kohli R, Kirby M, Xanthakos SA, Softic S, Feldstein AE, Saxena V, Tang PH, Miles L, Miles MV, Balistreri WF, Woods SC, Seeley RJ. High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis. Hepatology. 2010;52:934–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Wada T, Kenmochi H, Miyashita Y, Sasaki M, Ojima M, Sasahara M, Koya D, Tsuneki H, Sasaoka T. Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. Endocrinology. 2010;151:2040–9.

    Article  CAS  PubMed  Google Scholar 

  52. Kashireddy PV, Rao MS. Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis. Hepatol Res. 2004;30:104–10.

    Article  CAS  PubMed  Google Scholar 

  53. Tous M, Ferre N, Camps J, Riu F, Joven J. Feeding apolipoprotein E-knockout mice with cholesterol and fat enriched diets may be a model of non-alcoholic steatohepatitis. Mol Cell Biochem. 2005;268:53–8.

    Article  CAS  PubMed  Google Scholar 

  54. Sundaram SS, Whitington PF, Green RM. Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1321–7.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Yoshihisa Takahashi MD, Yurie Soejima MHSc & Toshio Fukusato MD

Authors
  1. Yoshihisa Takahashi MD
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  2. Yurie Soejima MHSc
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  3. Toshio Fukusato MD
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Corresponding author

Correspondence to Yoshihisa Takahashi MD .

Editor information

Editors and Affiliations

  1. Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland, USA

    Gerard E. Mullin

  2. Weight Management Center, Johns Hopkins Hospital, Baltimore, Maryland, USA

    Lawrence J. Cheskin

  3. Division of Gastroenterology and Hepatology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA

    Laura E. Matarese

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Takahashi, Y., Soejima, Y., Fukusato, T. (2014). Animal Models for Nonalcoholic Fatty Liver Disease. In: Mullin, G., Cheskin, L., Matarese, L. (eds) Integrative Weight Management. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0548-5_6

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  • DOI: https://doi.org/10.1007/978-1-4939-0548-5_6

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