Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612749
Poster Visit Session III Metabolism and Transport – Friday, January 26, 2018, 4:30pm – 5:15pm, Foyer area East Wing
Georg Thieme Verlag KG Stuttgart · New York

Dietary cholesterol promotes transition from hepatic steatosis to steatohepatitis/NASH particularly in combination with a PUFA-rich Western-type diet

J Henkel
1   University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal (Potsdam)
,
M Kuna
1   University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal (Potsdam)
,
D Coleman
1   University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal (Potsdam)
,
F Gellert
2   German Institute of Human Nutrition, Animal Facility, Nuthetal (Potsdam)
,
J Castro
3   German Institute of Human Nutrition, Department of Molecular Toxicology, Nuthetal (Potsdam)
,
G Püschel
1   University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal (Potsdam)
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

 

Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many animal models of NAFLD/NASH currently used 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). Dietary cholesterol is discussed to contribute to the transition from benign steatosis to the potentially fatal NASH. In the current study, C57BL/6 mice were fed a chow diet (STD), a Western-type diet containing soybean oil with high n-6-PUFA (SOD) or a comparable high-fat diet mainly consisting of lard (LAD), supplemented either without or with 0.75% cholesterol (SOD Cho, LAD Cho). In contrast to the SOD without cholesterol, both lard-based diets (LAD, LAD Cho) and the soybean-oil diet with cholesterol (SOD Cho) induced obesity and hepatic steatosis with a comparable increase in triglyceride accumulation.

However, only in the SOD Cho group in addition presented signs of inflammation and fibrosis. Although serum cholesterol levels were elevated in all 4 fatty diets, the hepatic cholesterol content was strongly increased solely in the SOD Cho group whereas cholesterol levels were mildly elevated in the LAD Cho group. Additionally, lipid peroxidation as a marker of mild oxidative stress and protein carbonylation as a marker for severe oxidative stress were more pronounced in livers of mice fed a n-6-PUFA-rich SOD/SOD Cho diet compared to the saturated fatty acid-rich LAD/LAD Cho diets. The resulting oxidative and ER stress triggered the release of proinflammatory cytokines and together with the accumulation of cholesterol rendered the hepatocyte more susceptible to apoptotic or necrotic cell death. Kupffer cells grouped around dying hepatocytes might be exposed to lipid peroxidation products and cholesterol released from hepatocytes. Kupffer cells, thus activated, can release proinflammatory, chemotactic and profibrotic cytokines that might promote inflammation and fibrosis. In accordance with this hypothesis, markers for immune cell infiltration, macrophage-recruiting chemokines, proinflammatory cytokines and markers for fibrosis were solely increased in livers of SOD Cho-fed mice resulting in a strong NASH phenotype.

By contrast, in livers of LAD Cho-fed mice markers for inflammation were only mildly increased while markers for fibrosis were not altered. Therefore, dietary cholesterol may be harmful to the liver, in particular when administered in combination with polyunsaturated fatty acids that favor lipid peroxidation