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Molecular Medicine

, Volume 23, Issue 1, pp 70–82 | Cite as

Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol

  • Janin Henkel
  • Charles Dominic Coleman
  • Anne Schraplau
  • Korinna Jöhrens
  • Daniela Weber
  • José Pedro Castro
  • Martin Hugo
  • Tim Julius Schulz
  • Stephanie Krämer
  • Annette Schürmann
  • Gerhard Paul Püschel
Research Article

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru- and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.

Notes

Acknowledgments

The excellent technical work of Manuela Kuna, Ines Grüner, Elisabeth Meyer and Susann Richter is gratefully acknowledged.

Supplementary material

10020_2017_2301070_MOESM1_ESM.pdf (537 kb)
Supplementary material, approximately 537 KB.

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Authors and Affiliations

  • Janin Henkel
    • 1
  • Charles Dominic Coleman
    • 1
  • Anne Schraplau
    • 1
  • Korinna Jöhrens
    • 2
  • Daniela Weber
    • 7
    • 10
  • José Pedro Castro
    • 6
    • 7
    • 8
    • 9
  • Martin Hugo
    • 7
  • Tim Julius Schulz
    • 3
    • 6
  • Stephanie Krämer
    • 4
  • Annette Schürmann
    • 5
    • 6
  • Gerhard Paul Püschel
    • 1
  1. 1.Department of Nutritional Biochemistry, Institute of Nutritional ScienceUniversity of PotsdamNuthetalGermany
  2. 2.Institute of PathologyCharité University Hospital BerlinBerlinGermany
  3. 3.Department of Adipocyte Development and NutritionGerman Institute of Human NutritionNuthetalGermany
  4. 4.Animal FacilityGerman Institute of Human NutritionNuthetalGermany
  5. 5.Department of Experimental DiabetologyGerman Institute of Human NutritionNuthetalGermany
  6. 6.German Center for Diabetes ResearchMünchen-NeuherbergGermany
  7. 7.Department of Molecular ToxicologyGerman Institute of Human NutritionNuthetalGermany
  8. 8.Faculty of Medicine, Department of BiomedicineUniversity of PortoPortoPortugal
  9. 9.Aging and Stress GroupInstitute for Innovation and Health ResearchPortoPortugal
  10. 10.NutriAct - Competence Cluster Nutrition Research Berlin-PotsdamNuthetalGermany

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