Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport

Article

关键词: HIGH-DENSITY-LIPOPROTEIN;    IN-VIVO;    DEFICIENT MICE;    SR-BI;    INCREASED ATHEROSCLEROSIS;    TRANSGENIC MICE;    HDL METABOLISM;    APOE;    DIET;    MUTATION;   

DOI  :  10.1161/CIRCULATIONAHA.107.704254

来源: SCIE

【 摘 要 】

Background - Cholesteryl ester transfer protein ( CETP) transfers cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B - containing lipoproteins and in humans plays an important role in lipoprotein metabolism. However, the role that CETP plays in mediation of reverse cholesterol transport (RCT) remains unclear. We used a validated in vivo assay of macrophage RCT to test the effect of CETP expression in mice ( which naturally lack CETP) on macrophage RCT, including in mice that lack the low-density lipoprotein receptor or the scavenger receptor class B, type I. Method and Results - A vector based on adeno-associated virus serotype 8 (AAV8) with a liver-specific thyroglobulin promoter was used to stably express human CETP in livers of mice and was compared with an AAV8-lacZ control vector. The RCT assay was performed 4 weeks after vector injection and involved the intraperitoneal injection of acetylated low-density lipoprotein cholesterol - loaded and H-3-cholesterol - labeled J774 macrophages in mice with plasma sampling at several time points, liver and bile sampling at 48 hours, and continuous fecal collection to measure H-3-sterol as an integrated readout of macrophage RCT. In apobec-1 - null mice, CETP expression reduced plasma high-density lipoprotein cholesterol levels but significantly increased fecal H-3-sterol excretion. In low-density lipoprotein receptor/apobec-1 double-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and had no effect on fecal H-3-sterol excretion. Finally, in scavenger receptor class B, type I - null mice, CETP expression reduced high-density lipoprotein cholesterol levels and significantly increased fecal H-3-sterol excretion. Conclusion - The present results demonstrate that CETP expression promotes macrophage RCT in mice, that this effect is dependent on the low-density lipoprotein receptor, and that CETP expression restores to normal the impaired RCT in mice deficient in scavenger receptor class B, type I.

【 授权许可】

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