Skip to main content
Log in

Feeding apolipoprotein E-knockout mice with cholesterol and fat enriched diets may be a model of non-alcoholic steatohepatitis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The present study was aimed (1) to investigate the effect of cholesterol and fat enriched diets on the development of steatohepatitis in apolipoprotein E-knockout mice, and (2) to study the chronological relationships between the development of hepatic alterations, hypercholesterolemia and atherosclerotic lesions in this experimental model. The study consisted of two protocols. Protocol 1 was used in 90 mice subdivided in groups of 18. For 10 weeks, each group was given a diet with different fat and cholesterol contents. Protocol 2 was used in 42 mice, subdivided in four groups. Each group was given a diet enriched with cholesterol and palm oil and they were sacrificed at 8, 13, 18 and 24 weeks of age. Results were as following. (1) Mice given high fat/high cholesterol diets developed an impairment of liver histology consisting of fat accumulation, macrophage proliferation, and inflammation. (2) These effects were modulated by the type of fat: olive oil was mainly associated with macrovesicular steatosis and cholesterol plus palm oil with severe steatohepatitis. (3) There was a chronological and quantitative relationship between liver impairment and the formation of atheromatous lesions. We conclude that apolipoprotein E-knockout mice may be a useful model for investigating the mechanisms of diet-induced steatohepatitis. (Mol Cell Biochem 268: 53–58, 2008)

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Moghadasian MH: Experimental atherosclerosis. A historical overview. Life Sci 70: 855–865, 2002

    Article  Google Scholar 

  2. Zhang SH, Reddick RL, Piedrahita JA, Maeda N: Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258: 468–471, 1992

    Google Scholar 

  3. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL: Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71: 343–353, 1992

    Article  Google Scholar 

  4. van Ree JH, van der Broek WJ, Dahlmans VE, Groot PH, Vidgeon-Hart M, Frants RR, Wieringa B, Havekes LM, Hofker MH: Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice. Atherosclerosis 111: 25–37, 1994

    Google Scholar 

  5. Hofker MH, van Vlijmen BJ, Havekes LM: Transgenic mouse models to study the role of ApoE in hyperlipidemia and atherosclerosis. Atherosclerosis 137: 1–11, 1998

    Article  Google Scholar 

  6. Moghadasian MH, Pritchard HP, McManus BM, Frohlich JJ: “Tall-oil” derived phytosterol mixture reduces atherosclerosis in apo E-deficient mice. Arterioscler Thromb Vasc Biol 17: 11, 1997

    Google Scholar 

  7. Osada J, Joven J, Maeda N: The value of apolipoprotein E knockout mice for studying the effects of dietary fat and cholesterol on atherogenesis. Curr Opin Lipidol 11: 25–29, 2000

    Article  Google Scholar 

  8. Tous M, Ferré N, Camps J, Joven J: Efectos de la dieta hipercolesterolemiante en el animal de experimentación. Clin Invest Arterioscler 14: 107, 2002

    Google Scholar 

  9. Koteish A, Diehl AM: Animal models of steatosis. Sem Liver Dis 21: 89–104, 2001

    Article  Google Scholar 

  10. Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N: Generation of mice carrying a mutant apolipoprotein E-gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci USA 82: 4471–4475, 1992

    Google Scholar 

  11. Calleja L, París MA, Paul A, Vilella E, Joven J, Jiménez A, Beltran G, Uceda M, Maeda N, Osada J: Low-cholesterol and high-fat diets reduce atherosclerotic lesion development in apoE-knockout mice. Arterioscler Thromb Vasc Biol 19: 2368–2375, 1999

    Google Scholar 

  12. Laurila A, Cole SP, Merat S, Obonyo M, Palinski W, Fierer J, Witztum JL: High-fat, high-cholesterol diet increases the incidence of gastritis in LDL receptor-negative mice. Arterioscler Thromb Vasc Biol, 21: 991–996, 2001

    Google Scholar 

  13. Tangirala RK, Rubin EM, Palinski Q: Quantitation of atherosclerosis in murine models: Correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesion between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J Lipid Res 36: 2320–2328, 1995

    CAS  PubMed  Google Scholar 

  14. Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA: Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68: 231–240, 1987

    Google Scholar 

  15. Vilella E, Joven J, Fernandez M, Vilaró S, Brunzell JD, Olivecrona T, Bengtsson-Olivecrona G: Lipoprotein lipase in human plasma is mainly inactive and associated with cholesterol-rich lipoproteins. J Lipid Res 34: 1555–1564, 1993

    Google Scholar 

  16. Ludwig J, Viggiano TR, McGill DB, Ott BJ: Non-alcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55: 434–438, 1980

    CAS  PubMed  Google Scholar 

  17. Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis. Med Clin North Am 80: 1147–1166, 1996

    Google Scholar 

  18. Ludwig J, McGill DB, Lindor KD: Review: Nonalcoholic steatohepatitis. J Gastroenterol Hepatol 12: 398–403, 1997

    Google Scholar 

  19. Baffy G, Zhang CY, Glickman JN, Lowell BB: Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology 35: 753–761, 2002

    Google Scholar 

  20. Brunt EM, Janney CG, Di Besceglie AM, Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am J Gastroentrol 94: 2467–2474, 1999

    Google Scholar 

  21. Yang SQ, Lin HZ, Hwang J, Chacko VP, Diehl AM: Hepatic hyperplasia in noncirrhotic fatty livers: Is obesity-related hepatic steatosis a premalignant condition? Cancer Res 61: 5016–5023, 2001

    Google Scholar 

  22. Koteish A, Diehl AM: Animal models of steatohepatitis. Best Practice Res Clin Gastroenterol 16: 679–690, 2002

    Google Scholar 

  23. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL: Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 98: 1575–1584, 1996

    Google Scholar 

  24. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS: Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREP-1c in adipose tissue: Model for congenital generalized lipodystrophy. Genes Dev 12: 3182s–3194s, 1998

    Google Scholar 

  25. Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C: Life without white fat: A transgenic mouse. Genes Dev 12: 3168–3181, 1998

    CAS  PubMed  Google Scholar 

  26. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM: Obesity increases sensitivity to endotoxin liver injury: Implications for pathogenesis of steatohepatitis. Proc Natl Acad Sci USA 94: 2557–2562, 1997

    Google Scholar 

  27. Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, Walajtys-Rode E, Rashid A, Chen CH, Huang CC, Wu TC, Lane MD, Diehl AM: Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 274: 5692–5700, 1999

    Google Scholar 

  28. Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA, Feingold KR, Grunfeld C: Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am J Physiol 276: R136–R142, 1999

    Google Scholar 

  29. Poulsom R: Morphological changes of organs after sucrose or fructose feeding. Progr Biochem Pharmacol 21: 104–134, 1986

    Google Scholar 

  30. Kuipers F, van Ree JM, Hofker MH, Wolters H, In’t Veld G, Havinga R, Vonk RJ, Princen HM, Havekes LM: Altered lipid metabolism in apolipoprotein E-deficient mice does not affect cholesterol balance across the liver. Hepatology 24: 241–247, 1996

    Google Scholar 

  31. Sehayek E, Shefer S, Nguyen LB, Ono JG, Merkel M, Breslow JL: Apolipoprotein E regulates dietary cholesterol absorption and biliary cholesterol excretion: Studies in C57BL/6 apolipoprotein E knockout mice. Proc Natl Acad Sci USA 97: 3433–3437, 2000

    Google Scholar 

  32. Ferré N, Camps J, Paul A, Cabré M, Calleja L, Osada J, Joven J: Effects of high-fat, low-cholesterol diets on hepatic lipid peroxidation and antioxidants in apolipoprotein E-deficient mice. Mol Cell Biochem 218: 165–169, 2001

    Google Scholar 

  33. Diehl AM: Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. Am J Physiol Gastrointest Liver Physiol 282: G1–G5, 2002

    Google Scholar 

  34. Pessayre D, Mansouri A, Fromenty B: Nonalcoholic steatosis and steatohepatitis V. Mitochondrial dysfunction in steatohepatitis. Am J Physiol Gastrointest Liver Physiol 282: G193–G199, 2002

    Google Scholar 

  35. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN: Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120: 1183–1192, 2001

    Google Scholar 

  36. Chitturi S, Farrell GC: Ethiopathogenesis of nonalcoholic steatohepatitits. Sem Liver Dis 21: 27–41, 2001

    Google Scholar 

  37. Liao F, Andalibi A, Qiao JH, Allayee H, Fogelman AM, Lusis AJ: Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J Clin Invest 94: 877–884, 1994

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jordi Camps.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tous, M., Ferré, N., Camps, J. et al. Feeding apolipoprotein E-knockout mice with cholesterol and fat enriched diets may be a model of non-alcoholic steatohepatitis. Mol Cell Biochem 268, 53–58 (2005). https://doi.org/10.1007/s11010-005-2997-0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-005-2997-0

Key words

Navigation