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

      Abstract

      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.

      Abbreviations:

      apoB (apolipoprotein B), ER (endoplasmic reticulum), FF (fructose-fed), HDL (high density lipoproteins), LDL (low density lipoproteins), MEM (minimum essential medium), MTP (microsomal triglyceride transfer protein), PAGE (polyacrylamide gel electrophoresis), PMSF (phenylmethylsulfonylfluoride), SDS (sodium dodecyl sulfate), SREBP (sterol regulatory element binding protein), VLDL (very low-density lipoproteins)

      Keywords

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