Abstract 11857: Reduction of Apolipoprotein E-rich HDL Levels with Berberine Stimulates Reverse Cholesterol Transport in Hyperlipidemic Hamsters Treated with CETP Inhibitor Torcetrapib
Objectives- Cholesteryl ester transfer protein (CETP) inhibition increases the levels of enlarged/apolipoprotein E rich HDL particles (apoE-HDL). Whether these particles are functional to promote reverse cholesterol transport (RCT) remains unclear. Here we investigated this issue in hyperlipidemic hamsters.
Methods and results- Hamsters were fed a hyperlipidemic diet, which increased non HDL-cholesterol levels and CETP activity by 258 and 54% after 4 weeks (both p<0.001 vs. chow fed hamsters). The diet also induced a severe liver steatosis, with a 50% reduction in LDL-receptor mRNA expression (p<0.001). A first group of hyperlipidemic hamsters were treated with torcetrapib at 30mg/kg (TOR) over 2 weeks. As expected, TOR significantly increased HDL-c levels by 35%, concomitant with the appearance of apoE-HDL, as shown by fast protein liquid chromatography. In vivo RCT was measured using 3H-cholesteryl oleate labeled oxLDL (3H-oxLDL) particles. After intravenous injection, 3H-oxLDL are rapidly cleared from plasma by liver resident macrophages, for further 3H-tracer egress in plasma, HDL, liver, bile and feces. TOR significantly increased 3H-tracer appearance in HDL by 30% over 72 hours after injection. However, 3H-tracer recovered in liver, bile and feces did not change, suggesting that uptake and excretion of cholesterol deriving from apoE-HDL particles is not enhanced under CETP inhibition. As apoE-HDL is a potent ligand for the LDL-receptor, we next evaluated the effects of TOR in combination with berberine, a natural compound that up-regulates LDL-receptor expression in hyperlipidemic hamsters. Compared to TOR alone, treatment with TOR+berberine 150mg/kg (TOR+BER) resulted in lower apoE-HDL levels, as expected. After 3H-oxLDL injection, 3H-tracer appearance tended to be lower in HDL but significantly higher (109%) in fecal cholesterol with TOR+BER vs. TOR. This effect was confirmed by the 97% increase of cholesterol mass excreted in feces with TOR+BER.
Conclusion- In hyperlipidemic hamsters, stimulating RCT under CETP inhibition requires up-regulation of LDL-receptor expression. These findings should be investigated in humans to evaluate the benefits of CETP inhibitors.
- © 2011 by American Heart Association, Inc.