Glucocorticoids have been implicated in the pathogenesis of all stages of non-alcoholic fatty liver disease (NAFLD). Natural killer T cells play a role in the pathogenesis of NAFLD and in the response to steroids. The aim of the present study was to determine the role of CD1d in steroid-mediated metabolic derangement and the steroid-protective effect of glycosphingolipids. Methods: Ten groups of mice were studied. Steroids were orally administered to C57BL/6 mice to assess the therapeutic effect of β-glucsylceramide (GC) on the development of steroid-mediated liver damage and metabolic derangements. The role of CD1d in the pathogenesis of steroid-induced liver damage, and in mediating the hepatoprotective effect of GC were studied in CD1d−/− mice. Results: A model of oral administration of steroids was established, resulting in insulin resistance, hyperinsulinemia, hypertriglyceridemia, liver steatosis, and hepatocellular injury. Steroid administration to CD1d−/− mice was associated with hyperglycemia and hypertriglyceridemia. However, CD1d−/− mice were relatively resistant to steroid-induced steatosis. GC treatment alleviated steroid-associated metabolic derangements and liver injury independent of CD1d expression. Conclusion: A steroid-mediated model of NAFLD and metabolic derangements was established in which steroid-mediated steatosis was CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes were CD1d-independent, further supporting a dichotomy between steatosis and steatohepatitis in NAFLD.
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