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.
Highlights
Apart from being the central organ for maintenance of glucose homeostasis [1], the liver plays a pivotal role in lipid metabolism [2]
Hepatic steatosis is one feature of nonalcoholic fatty liver disease (NAFLD), which can be complicated by low-grade inflammation and fibrosis in nonalcoholic steatohepatitis (NASH), which in the long run can give rise to liver cirrhosis and hepatocellular carcinoma [3]
Animals were fed [1] a standard chow diet (8% of the calories derived from fat) as a control (STD), [2] a Western-type diet with 43% of the calories derived from soybean oil (25 g/100 g) with a high content of n-6-PUFAs such as linoleic acid (13,2 g/100 g), [3] a Western-type diet similar to [2] that contained 0.75% cholesterol and [4] a lard-containing high-fat diet with 45% of the calories mainly from fat with saturated fatty acids (21 g/100 g lard) and a minor fraction of n-6-PUFA (3 g/100 g soybean oil) supplemented with 5% fructose in drinking water
Summary
Apart from being the central organ for maintenance of glucose homeostasis [1], the liver plays a pivotal role in lipid metabolism [2]. Many animal models currently used to study NAFLD fail to reproduce all clinical, biochemical and morphological features of human NASH [7] Genetic obesity models, such as ob/ob or db/db mice, display steatosis and are insulin resistant but appear to be protected from the development of inflammation and fibrosis [8]. When added to a high-fat diet, both fructose [11] and cholesterol [12] as well as increased n-6-polyunsaturated fatty acid (n-6-PUFA) in the fat content [13,14] seem to favor development of liver steatosis and insulin resistance or inflammation and fibrosis. In the current study, three high-fat diets differing in their fatty acid composition as well as cholesterol and fructose content were compared for their impact on weight gain, insulin resistance and development of NASH
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