Rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

International Journal of Molecular Sciences

Volumn 14, Issue 11, 2013, Pages 21833-21857

  Imajo, Kento ^a   Yoneda, Masato ^a   Kessoku, Takaomi ^a   Ogawa, Yuji ^a   Maeda, Shin ^a   Sumida, Yoshio ^b   Hyogo, Hideyuki ^c   Eguchi, Yuichiro ^d   Wada, Koichiro ^e   Nakajima, Atsushi ^a  

^a YOKOHAMA CITY UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b KYOTO PREFECTURAL UNIVERSITY OF MEDICINE   (Japan)

^c HIROSHIMA UNIVERSITY   (Japan)

^d SAGA UNIVERSITY   (Japan)

^e OSAKA UNIVERSITY   (Japan)

Author keywords

Animal model; NAFLD; NASH; Rodent model

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; CHOLECYSTOKININ A RECEPTOR; CHYLOMICRON; ENDOTOXIN; FATTY ACID; FRUCTOSE; GLUCOCORTICOID; INTERLEUKIN 1; LEPTIN; LIPOPROTEIN LIPASE; STAT5 PROTEIN; STEROL REGULATORY ELEMENT BINDING PROTEIN; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR; VERY LOW DENSITY LIPOPROTEIN;

ADIPOSE TISSUE; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANIMAL BEHAVIOR; CHOLESTEROL LIVER LEVEL; CHOLESTEROL METABOLISM; DIETARY INTAKE; DYSLIPIDEMIA; FATTY ACID BLOOD LEVEL; FATTY ACID METABOLISM; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; GLUCOSE TOLERANCE; HEPATITIS; HYPERGLYCEMIA; HYPERINSULINEMIA; HYPERLIPIDEMIA; INSULIN RESISTANCE; LEPTIN DEFICIENCY; LIPID DIET; LIPID METABOLISM; LIPOGENESIS; LIVER FATTY DEGENERATION; METABOLIC SYNDROME X; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; OTSUKA LONG EVANS TOKUSHIMA FATTY RAT; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN EXPRESSION; REVIEW; RODENT MODEL;

ANIMALS; DISEASE MODELS, ANIMAL; FATTY LIVER; HUMANS; MICE; RATS;

EID: 84887187257     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms141121833     Document Type: Review

References (115)

1. Sanyal, A. J. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002, 123, 1705-1725.
2. Marchesini, G.; Bugianesi, E.; Forlani, G.; Cerrelli, F.; Lenzi, M.; Manini, R.; Natale, S.; Vanni, E.; Villanova, N.; Melchionda, N.; et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003, 37, 917-923.
3. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 2002, 346, 1221-1231.
4. Clark, J. M.; Brancati, F. L.; Diehl, A. M. Nonalcoholic fatty liver disease. Gastroenterology 2002, 122, 1649-1657.
5. Neuschwander-Tetri, B. A.; Caldwell, S. H. Nonalcoholic steatohepatitis, summary of an AASLD single topic conference. Hepatology 2003, 37, 1202-1219.
6. Day, C. P. Non-alcoholic steatohepatitis (NASH), where are we now and where are we going? Gut 2002, 50, 585-588.
7. Fan, J.-G.; Li, F.; Cai, X.-B.; Peng, Y.-D.; Ao, Q.-H.; Gao, Y. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J. Gastroenterol. Hepatol. 2007, 22, 1086-1091.
8. Harrison, S. A.; Torgerson, S.; Hayashi, P. H. The natural history of nonalcoholic fatty liver disease, a clinical histopathological study. Am. J. Gastroenterol. 2003, 98, 2042-2047.
9. Day, C. P.; Saksena, S. Non-alcoholic steatohepatitis, definitions and pathogenesis. J. Gastroenterol. Hepatol. 2002, 17, 377-384.
10. Powell, E. E.; Cooksley, W. G.; Hanson, R.; Searle, J.; Halliday, J. W.; Powell, L. W. The natural history of nonalcoholic steatohepatitis, a follow-up study of forty-two patients for up to 21 years. Hepatology 1990, 11, 74-80.
11. Day, C. P.; James, O. F. Steatohepatitis, a tale of two "hits"? Gastroenterology 1998, 114, 842-845.
12. Tilg, H.; Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 2010, 52, 1836-1846.
13. Day, C. P. Pathogensis of steatohepatitis. Best Pract. Res. Clin. Gastroenterol. 2002, 16, 663-678.
14. London, R. M.; George, J. Pathogenesis of NASH, animal models. Clin. Liver Dis. 2007, 11, 55-74.
15. Wanless, I. R.; Shiota, K. The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases, a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis. Semin. Liver Dis. 2004, 24, 99-106.
16. Farrell, G. C.; Larter, C. Z. Nonalcoholic fatty liver disease, from steatosis to cirrhosis. Hepatology 2006, 43, 99-112.
17. Cohen, J. C.; Horton, J. D.; Hobbs, H. H. Human fatty liver disease: Old questions and new insights. Science 2011, 332, 1519-1523.
18. Fan, J. G.; Xu, Z. J.; Wang, G. L. Effect of lactulose on establishment of a rat non-alcoholic steatohepatitis model. World J. Gastroenterol. 2005, 11, 5053-5056.
19. Larter, C. Z. Not all models of fatty liver are created equal, understanding mechanisms of steatosis development is important. J. Gastroenterol. Hepatol. 2007, 22, 1353-1354.
20. Koteish, A.; Diehl, A. M. Animal models of steatosis. Semin. Liver Dis. 2001, 21, 89-104.
21. Donnelly, K. L.; Smith, C. I.; Schwarzenberg, S. J.; Jessurun, J.; Boldt, M. D.; Parks, E. J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343-1351.
22. Nehra, V.; Angulo, P.; Buchman, A. L.; Lindor, K. D. Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis. Dig. Dis. Sci. 2001, 46, 2347-2352.
23. Bradbury, M. W. Lipid metabolism and liver inflammation. Hepatic fatty acid uptake-possible role in steatosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, 194-198.
24. Petersen, K. F.; Dufour, S.; Befroy, D.; Lehrke, M.; Hendler, R. E.; Shulman, G. I. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005, 54, 603-608.
25. Previs, S. F.; Withers, D. J.; Ren, J. M.; White, M. F.; Shulman, G. I. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J. Biol. Chem. 2000, 275, 38990-38904.
26. Utzschneider, K. M.; Kahn, S. E. The role of insulin resistance in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 2006, 91, 4753-4761.
27. Abdelmalek, M. F.; Diehl, A. M. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med. Clin. N. Am. 2007, 91, 1125-1149.
28. Kim, J. K.; Michael, M. D.; Previs, S. F.; Peroni, O. D.; Mauvais-Jarvis, F.; Neschen, S.; Kahn, B. B.; Kahn, C. R.; Shulman, G. I. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J. Clin. Investig. 2000, 105, 1791-1797.
29. Koch, L.; Wunderlich, F. T.; Seibler, J.; Konner, A. C.; Hampel, B.; Irlenbusch, S.; Brabant, G.; Kahn, C. R.; Schwenk, F.; Brüning, J. C. Central insulin action regulates peripheral glucose and fat metabolism in mice. J. Clin. Investig. 2008, 118, 2132-2147.
30. Blüher, M.; Michael, M. D.; Peroni, O. D.; Ueki, K.; Carter, N.; Kahn, B. B.; Kahn, C. R. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev. Cell 2002, 3, 25-38.
31. Reddy, J. K.; Rao, M. S. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, 852-858.
32. Ito, M.; Suzuki, J.; Sasaki, M.; Watanabe, K.; Tsujioka, S.; Takahashi, Y.; Gomori, A.; Hirose, H.; Ishihara, A.; Iwaasa, H.; et al. Development of nonalcoholic steatohepatitis model through combination of high-fat diet and tetracycline with morbid obesity in mice. Hepatol. Res. 2006, 34, 92-98.
33. Ito, M.; Suzuki, J.; Tsujioka, S.; Sasaki, M.; Gomori, A.; Shirakura, T.; Hirose, H.; Ito, M.; Ishihara, A.; Iwaasa, H.; et al. Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. Hepatol. Res. 2007, 37, 50-57.
34. Deng, Q. G.; She, H.; Cheng, J. H.; French, S. W.; Koop, D. R.; Xiong, S.; Tsukamoto, H. Steatohepatitis Induced by Intragastric overfeeding in mice. Hepatology 2005, 42, 905-914.
35. Tetri, L. H.; Basaranoglu, M.; Brunt, E. M.; Yerian, L. M.; Neuschwander-Tetri, B. A. 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, 987-995.
36. Tsuchiya, H.; Ebata, Y.; Sakabe, T. High-fat, high-fructose diet induces hepatic iron overload via a hepcidin-independent mechanism prior to the onset of liver steatosis and insulin resistance in mice. Metabolism 2013, 62, 62-69.
37. Bergheim, I.; Weber, S.; Vos, M. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: Role of endotoxin. J. Hepatol. 2008, 48, 983-992.
38. Spruss, A.; Kanuri, G.; Wagnerberger, S.; Haub, S.; Bischoff, S. C.; Bergheim, I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 2009, 50, 1094-1104.
39. Kanuri, G.; Spruss, A.; Wagnerberger, S. Role of tumor necrosis factor alpha (TNFalpha) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J. Nutr. Biochem. 2011, 22, 527-534.
40. Tappy, L.; Le, K. A.; Tran, C. Fructose and metabolic diseases: New findings, new questions. Nutrition 2010, 26, 1044-1049.
41. Ingalls, A. M.; Dickie, M. M.; Snell, G. D. Obese, a new mutation in the house mouse. J. Hered. 1950, 41, 317-318.
42. Mayer, J.; Russell, R. E.; bates, M. W.; dickie, M. M. Metabolic, nutritional and endocrine studies of the hereditary obesity-diabetes syndrome of mice and mechanism of its development. Metabolism 1953, 2, 9-21.
43. Garthwaite, T. L.; Martinson, D. R.; Tseng, L. F.; Hagen, T. C.; Menahan, L. A. A longitudinal hormonal profile of the genetically obese mouse. Endocrinology 1980, 107, 671-676.
44. Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.; Friedman, J. M. Positional cloning of the mouse obese gene and its human homolog. Nat. Dec. 1994, 372, 425-432.
45. Pelleymounter, M. A.; Cullen, M. J.; Baker, M. B.; Hecht, R.; Winters, D.; Boone, T.; Collins, F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995, 269, 540-543.
46. Halaas, J. L.; Gajiwala, K. S.; Maffei, M.; Cohen, S. L.; Chait, B. T.; Rabinowitz, D.; Lallone, R. L.; Burley, S. K.; Friedman, J. M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995, 269, 543-546.
47. Lindström, P. The physiology of obese-Hyperglycemic mice (ob/ob mice). Sci. World J. 2007, 29, 666-685.
48. Hummel, K. P.; Dickie, M. M.; Coleman, D. L. Diabetes, a new mutation in the mouse. Science 1966, 153, 1127-1128.
49. Tartaglia, L. A.; Dembski, M.; Weng, X.; Deng, N.; Culpepper, J.; Devos, R.; Richards, G. J.; Campfield, L. A.; Clark, F. T.; Deeds, J. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995, 83, 1263-1271.
50. Wortham, M.; He, L.; Gyamfi, M.; Copple, B. L.; Wan, Y. J. 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, 2761-2774.
51. Takaya, K.; Ogawa, Y.; Isse, N.; Okazaki, T.; Satoh, N.; Masuzaki, H.; Mori, K.; Tamura, N.; Hosoda, K.; Nakao K. Molecular cloning of rat leptin receptor isoform complementary DNAs-identification of a missense mutation in zucker fatty (fa/fa) rats. Biochem. Biophys. Res. Commun. 1996, 225, 75-83.
52. Balthasar, N.; Dalgaard, L. T.; Lee, C. E. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005, 123, 493-505.
53. Itoh, M.; Suganami, T.; Nakagawa, N. Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am. J. Pathol. 2011, 179, 2454-2463.
54. Vaisse, C.; Clement, K.; Durand, E. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Investig. 2000, 106, 253-262.
55. Jiang, L.; You, J.; Yu, X.; Gonzalez, L.; Yu, Y.; Wang, Q.; Yang, G.; Li, W.; Li, C.; Liu, Y. Tyrosine-dependent and-independent actions of leptin receptor in control of energy balance and glucose homeostasis. EPUB 2008, 105, 18619-18624.
56. Piper, M. L.; Unger, E. K.; Myers, M. G., Jr.; Xu, A. W. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol. Endocrinol. 2008, 22, 751-759.
57. Bates, S. H.; Kulkarni, R. N.; Seifert, M.; Myers, M. G., Jr. Roles for leptin receptor/STAT3-dependent and-independent signals in the regulation of glucose homeostasis. Cell Metab. 2005, 1, 169-178.
58. 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 KKAy mice. Hepatol. Res. 2006, 36, 217-228.
59. Soga, M.; Hashimoto, S.; Kishimoto, Y.; Hirasawa, T.; Makino, S.; Inagaki, S. Insulin resistance, steatohepatitis, and Hepatocellular carcinoma in a New Congenic Strain of fatty liver Shionogi (FLS) with the Lepob gene. Exp. Anim. 2010, 59, 407-419.
60. Kawano, K.; Hirashima, T.; Mori, S.; Saitoh, Y.; Kurosumi, M.; Natori, T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992, 42, 1422-1428.
61. Nielsen, S.; Guo, Z.; Johnson, C. M.; Hensrud, D. D.; Jensen, M. D. Splanchnic lipolysis in human obesity. J. Clin. Investig. 2004, 113, 1582-1588.
62. Shimomura, I.; Hammer, R. E.; Richardson, J. A.; Ikemoto, S.; Bashmakov, Y.; Goldstein, J. L.; Brown, M. S. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue, model for congenital generalized lipodystrophy. Genes Dev. 1998, 12, 3182-3194.
63. Moitra, J.; Mason, M. M.; Olive, M.; Krylov, D.; Gavrilova, O.; Marcus-Samuels, B.; Feigenbaum, L.; Lee, E.; Aoyama, T.; Eckhaus, M. Life without white fat, a transgenic mouse. Genes Dev. 1998, 12, 3168-3181.
64. Coburn, C. T.; Knapp, F. F., Jr.; Febbraio, M.; Beets, A. L.; Silverstein, R. L.; Abumrad, N. A. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J. Biol. Chem. 2000, 275, 32523-32529.
65. Ross, S. R.; Graves, R. A.; Spiegelman, B. M. Targeted expression of a toxin gene to adipose tissue, transgenic mice resistant to obesity. Genes Dev. 1993, 7, 1318-1324.
66. Koutnikova, H.; Cock, T. A.; Watanabe, M.; Houten. S. M.; Champy, M. F.; Dierich, A.; Auwerx, J. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR hypomorphic mice. Proc. Natl. Acad. Sci. USA 2003, 100, 14457-14462.
67. Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper, M. S.; Hewison, M.; Stewart, P. M. 11beta-hydroxysteroid dehydrogenase type 1, a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 2004, 25, 831-866.
68. Morton, N. M.; Seckl, J. R. 11beta-hydroxysteroid dehydrogenase type 1 and obesity. Front. Horm. Res. 2008, 36, 146-164.
69. Laurent, V.; Kimble, A.; Peng, B.; Zhu, P.; Pintar, J. E.; Steiner, D. F.; Lindberg, I. Mortality in 7B2 null mice can be rescued by adrenalectomy, involvement of dopamine in ACTH hypersecretion. Proc. Natl. Acad. Sci. USA 2002, 99, 3087-3092.
70. Gilham, D.; Perreault, K. R.; Holmes, C. F.; Brindley, D. N.; Vance, D. E.; Lehner, R. Insulin, glucagon and fatty acid treatment of hepatocytes does not result in phosphorylation or changes in activity of triacylglycerol hydrolase. Biochim. Biophys. Acta 2005, 1736, 189-199.
71. Rossetti, L.; Barzilai, N.; Chen, W.; Harris, T.; Yang, D.; Rogler, C. E. Hepatic overexpression of insulin-like growth factor-II in adulthood increases basal and insulin-stimulated glucose disposal in conscious mice. J. Biol. Chem. 1996, 271, 203-208.
72. Zhou, Y. C.; Davey, H. W.; McLachlan, M. J.; Xie, T.; Waxman, D. J. Elevated basal expression of liver peroxisomal beta-oxidation enzymes and CYP4A microsomal fatty acid omega-hydroxylase in STAT5b-/-mice, cross-talk in vivo between peroxisome proliferator-activated receptor and signal transducer and activator of transcription signaling pathways. Toxicol. Appl. Pharmacol. 2002, 182, 1-10.
73. Browning, J. D.; Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Investig. 2004, 114, 147-152.
74. Foufelle, F.; Ferre, P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose, a role for the transcription factor sterol regulatory element binding protein-1c. Biochem. J. 2002, 366, 377-391.
75. Trumble, G.; Smith, M.; Winder, W. Purification and characterization of rat skeletal muscle acetyl-CoA carboxylase. Eur. J. Biochem. 1995, 231, 192-198.
76. Nosadini, R.; Ursini, F.; Tessari, P.; Tiengo, A.; Gregolin, C. Perfused liver carnitine palmitoyl-transferase activity and ketogenesis in streptozotocin treated and genetic hyperinsulinemic rats. Effect of glucagon. Horm. Metab. Res. 1979, 11, 661-664.
77. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S. I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275, 1943-1947.
78. Maehama, T.; Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J. Biol. Chem. 1998, 273, 13375-13378.
79. Horie, Y.; Suzuki, A.; Kataoka, E.; Sasaki, T.; Hamada, K.; Sasaki, J.; Mizuno, K.; Hasegawa, G.; Kishimoto, H.; Iizuka, M.; et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J. Clin. Investig. 2004, 113, 1774-1783.
80. Koh, H. J.; Lee, S. M.; Son, B. G.; Lee, S. H.; Ryoo, Z. Y.; Chang, K. T.; Park, J.-W.; Park, D.-C.; Song, B. J.; Veech, R. L.; et al. Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J. Biol. Chem. 2004, 279, 39968-39974.
81. Iizuka, K.; Bruick, R. K.; Liang, G.; Horton, J. D.; Uyeda, K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc. Natl. Acad. Sci. USA 2004, 101, 7281-7286.
82. Takahashi, A.; Shimano, H.; Nakagawa, Y.; Yamamoto, T.; Motomura, K.; Matsuzaka, T.; Sone, H.; Suzuki, H.; Toyoshima, H.; Yamada, N.; et al. Transgenic mice overexpressing SREBP-1a under the control of the PEPCK promoter exhibit insulin resistance, but not diabetes. Biochim. Biophys. Acta 2005, 1740, 427-433.
83. Bennett, M. J. Pathophysiology of fatty acid oxidation disorders. J. Inherit. Metab. Dis. 2009, 33, 533-537.
84. McGarry, J. D.; Brown, N. F. The mitochondrial carnitine palmitoyltransferase system, from concept to molecular analysis. Eur. J. Biochem. 1997, 244, 1-6.
85. Yanagitani, A.; Yamada, S.; Yasui, S.; Shimomura, T.; Murai, R.; Murawaki, Y.; Hashiguchi, K.; Kanbe, T.; Saeki, T.; Ichiba, M.; et al. Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice. Hepatology 2004, 40, 366-375.
86. Fan, C. Y.; Pan, J.; Usuda, N.; Yeldandi, A. V.; Rao, M. S.; Reddy, J. K. Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J. Biol. Chem. 1998, 273, 15639-15645.
87. Aoyama, T.; Peters, J. M.; Iritani, N.; Nakajima, T.; Furihata, K.; Hashimoto, T.; Gonzalez, F. J. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J. Biol. Chem. 1998, 273, 5678-5684.
88. Nemoto, Y.; Toda, K.; Ono, M.; Adachi, K. F.; Saibara, T.; Onishi, S.; Enzan, H.; Okada, T.; Shizuta, Y. Altered expression of fatty acid-metabolizing enzymes in aromatase deficient mice. J. Clin. Investig. 2000, 105, 1819-1825.
89. Kuwajima, M.; Kono, N.; Horiuchi, M.; Imamura, Y.; Ono, A.; Inui, Y.; Kawata, S.; Koizumi, T.; Hayakawa, J.; Saheki, T.; et al. Animal model of systemic carnitine deficiency: Analysis in C3H-H-2 degrees strain of mouse associated with juvenile visceral steatosis. Biochem. Biophys. Res. Commun. 1991, 174, 1090-1094.
90. Boison, D.; Scheurer, L.; Zumsteg, V.; Rülicke, T.; Litynski, P.; Fowler, B.; Brandner, S.; Mohler, H. Neonatal hepatic steatosis by disruption of the adenosine kinase gene. Proc. Natl. Acad. Sci. USA 2002, 99, 6985-6990.
91. Hamelet, J.; Demuth, K.; Paul, J. L.; Delabar, J. M.; Janel, N. Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice. Hepatology 2007, 46, 151-159.
92. Arsov, T.; Larter, C. Z.; Nolan, C. J.; Petrovsky, N.; Goodnow, C. C.; Teoh, N. C.; Yeh, M. M.; Farrell, G. C. Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice. Biochem. Biophys. Res. Commun. 2006, 342, 1152-1159.
93. Julius, U. Influence of plasma free fatty acids on lipoprotein synthesis and diabetic dyslipidemia. Exp. Clin. Endocrinol. Diabetes 2003, 111, 246-250.
94. Gordon, D. A. Recent advances in elucidating the role of the microsomal triglyceride transfer protein in apolipoprotein B lipoprotein assembly. Curr. Opin. Lipidol. 1997, 8, 131-137.
95. Wetterau, J. R.; Gregg, R. E.; Harrity, T. W.; Arbeeny, C.; Cap, M.; Connolly, F.; Chu, C. H.; George, R. J.; Gordon, D. A.; Jamil, H.; et al. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 1998, 282, 751-754.
96. Rinella, M. E.; Elias, M. S.; Smolak, R. R.; Fu, T.; Borensztajn, J.; Green, R. M. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J. Lipid Res. 2008, 49, 1068-1076.
97. Raabe, M.; Véniant, M. M.; Sullivan, M. A.; Zlot, C. H.; Björkegren, J.; Nielsen, L. B.; Wong, J. S.; Hamilton, R. L.; Young, S. G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J. Clin. Investig. 1999, 103, 1287-1298.
98. Helmkamp, G. M., Jr.; Harvey, M. S.; Wirtz, K. W.; Van Deenen, L. L. Phospholipid exchange between membranes. Purification of bovine brain proteins that preferentially catalyze the tranfer of phosphatidylinositol. J. Biol. Chem. 1974, 249, 6382-6389.
99. Alb, J. G., Jr.; Cortese, J. D.; Phillips, S. E.; Albin, R. L.; Nagy, T. R.; Hamilton, B. A.; Bankaitis V. A. Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia. J. Biol. Chem. 2003, 278, 33501-33518.
100. Zhu, X.; Song, J.; Mar, M. H.; Edwards, L. J.; Zeisel, S. H. Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline. Biochem. J. 2003, 370, 987-993.
101. Hussain, M. M.; Maxfield, F. R.; Más-Oliva, J.; Tabas, I.; Ji, Z. S.; Innerarity, T. L.; Mahley, R. W. Clearance of chylomicron remnants by the low density ipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J. Biol. Chem. 1991, 266, 13936-13940.
102. Ma, K. L.; Ruan, X. Z.; Powis, S. H.; Chen, Y.; Moorhead, J. F.; Varghese, Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 2008, 48, 770-781.
103. Vlahcevic, Z. R.; Stravitz, R. T.; Heuman, D. M.; Hylemon, P. B.; Pandak, W. M. Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the rat. Gastroenterology 1997, 113, 1949-1957.
104. Feng, B.; Yao, P. M.; Li, Y.; Devlin, C. M.; Zhang, D.; Harding, H. P.; Sweeney, M.; Rong, J. X.; Kuriakose, G.; Fisher, E. A.; et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat. Cell Biol. 2003, 5, 781-792.
105. Devries-Seimon, T.; Li, Y.; Yao, P. M.; Stone, E.; Wang, Y.; Davis, R. J.; Flavell, R.; Tabas, I. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J. Cell. Biol. 2005, 171, 61-73.
106. Bieghs, V.; Verheyen, F.; van, Gorp, P. J.; Hendrikx, T.; Wouters, K.; Lütjohann, D.; Gijbels, M. J.; Febbraio, M.; Binder, C. J.; Hofker, M. H.; et al. Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells. PLoS One 2012, 7, e34378.
107. Puri, P.; Baillie, R. A.; Wiest, M. M.; Mirshahi, F.; Choudhury, J.; Cheung, O.; Sargeant, C.; Contos, M. J.; Sanyal, A. J. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007, 46, 1081-1090.
108. Isoda, K.; Sawada, S.; Ayaori, M.; Matsuki, T.; Horai, R.; Kagata, Y.; Miyazaki, K.; Kusuhara, M.; Okazaki, M.; Matsubara, O. Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice. J. Biol. Chem. 2005, 280, 7002-7009.
109. Otogawa, K.; Kawada, N. A rabbit model for the study of human NASH. Nippon Rinsho 2006, 64, 1043-1047.
110. Matteoni, C. A.; Younossi, Z. M.; Gramlich, T.; Boparai, N.; Liu, Y. C.; McCullough, A. J. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 1999, 116, 1413-1419.
111. Brunt, E. M.; Neuschwander-Tetri, B. A.; Oliver, D.; Wehmeier, K. R.; Bacon, B. R. Nonalcoholic steatohepatitis: Histologic features and clinical correlations with 30 blinded biopsy specimens. Hum. Pathol. 2004, 35, 1070-1082.
112. Burt, A. D.; Mutton, A.; Day, C. P. Diagnosis, interpretation of steatosis and steatohepatitis. Semin. Diagn. Pathol. 1998, 15, 246-258.
113. Yahagi, N.; Shimano, H.; Matsuzaka, T.; Sekiya, M.; Najima, Y.; Okazaki, S.; Okazaki, H.; Tamura, Y.; Iizuka, Y.; Inoue, N. p53 Involvement in the Pathogenesis of Fatty Liver Disease. J. Biol. Chem. 2004, 279, 20571-20575.
114. Xu, H.; Barnes, G. T.; Yang, Q.; Tan, G.; Yang, D.; Chou, C. J.; Sole, J.; Nichols, A.; Ross, J. S.; Tartaglia, L. A.; et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Investig. 2003, 112, 1821-1830.
115. Imajo, K.; Fujita, K.; Yoneda, M.; Nozaki, Y.; Ogawa, Y.; Shinohara, Y.; Kato, S.; Mawatari, H.; Shibata, W.; Kitani, H.; et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 2012, 16, 44-54.