Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the efficacy and mechanisms of action of rosuvastatin, a HMG-CoA reductase inhibitor, in ameliorating metabolic dyslipidemia in insulin-resistant states. Fructose feeding for a 2-week period induced insulin resistance and a significant increase in hepatic secretion of VLDL. This was followed by a fructose-enriched diet with or without 10 mg/kg rosuvastatin for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups (n = 6, p < 0.001). However, there was a significant decline (30%, n = 8, p < 0.05) in plasma triglyceride levels following rosuvastatin feeding (10 mg/kg). A significant decrease (n = 6, p < 0.05) was also observed in VLDL-apoB production in hepatocytes isolated from drug-treated hamsters, together with an increased apoB degradation (n = 6, p < 0.05). Similar results were obtained in parallel cell culture experiments in which primary hepatocytes were first isolated from chow-fed hamsters, and then treated in vitro with 15 μM rosuvastatin for 18 h. Rosuvastatin at 5 μM caused a substantial reduction in synthesis of unesterified cholesterol and cholesterol ester (98 and 25%, n = 9, p < 0.01 or p < 0.05) and secretion of newly synthesized unesterified cholesterol, cholesterol ester, and triglyceride (95, 42, and 60% reduction, respectively, n = 9, p < 0.01 or p < 0.05). This concentration of rosuvastatin also caused a significant reduction (75% decrease, n = 4, p < 0.01) in the extracellular secretion of VLDL-apoB100, accompanied by a significant increase in the intracellular degradation of apoB100. There was a 12% reduction (not significant, p > 0.05) in hepatic MTP and no changes in ER-60 (a chaperone involved in apoB degradation) protein levels. Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by rosuvastatin in a process involving enhanced apoB degradation. This appears to lead to a significant amelioration of hepatic VLDL-apoB overproduction observed in the fructose-fed, insulin-resistant hamster model.