Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters

摘要

Objective-This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters. Methods and Results-In vivo reverse cholesterol transport was measured after an intravenous injection of H-cholesteryl-oleate-labeled/ oxidized low density lipoprotein particles (H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E-rich HDL levels and significantly increased H-tracer appearance in HDL by 30% over 72 hours after H-oxLDL injection. However, TOR did not change H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After H-oxLDL injection, TOR+berberine significantly increased H-tracer appearance in fecal cholesterol by 109%. Conclusion-Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process.