Abstract 15213: Deletion of PLTP in SR-BI Knockout Mice Shifts Lipids from HDL to VLDL/LDL and Reduces Atherosclerosis
Introduction: Disruption of SR-BI in mice increases atherosclerosis susceptibility despite the accumulation of abnormally large HDL particles. Another important modulator of HDL remodeling is phospholipid transfer protein (PLTP). In this study the importance of PLTP for the accumulation of large HDL particles in SR-BI knockout (SR-BI KO) mice and the influence on the increased atherosclerosis susceptibility of these animals was investigated.
Methods and Results: SR-BI/PLTP double knockout (dKO) mice were generated by cross-breeding of SR-BI KO and PLTP KO mice and fed a Western-type diet (WTD) for 20 weeks to induce atherosclerosis. Absence of PLTP in SR-BI KO mice decreased serum cholesterol 1.7-fold (p<0.001, n=8) and phospholipids 1.4-fold (p<0.001, n=8). Furthermore, the distribution of cholesterol and phospholipids over the different lipoprotein particles had shifted from HDL to VLDL and LDL. In line with the observed increase in VLDL levels, SR-BI/PLTP dKO mice also displayed a 2.2-fold (p<0.001, n=8) increase in serum triglycerides. Furthermore, HDL particle size was normalized in the SR-BI/PLTP dKO mice. PLTP deficiency, however, did not normalize the impaired delivery of [3H]CE from HDL to the liver in SR-BI KO mice. Only 9.2±0.4 % of the injected dose (ID) of [3H]CE-HDL was taken up by the liver in SR-BI KO animals (n=3) and 9.1±1.2 %ID in SR-BI/PLTP dKO mice (n=3) at 24 hours after injection, as compared to 46±2.3 %ID in wild-type (WT) animals (n=3). Importantly, deletion of PLTP, partly normalized the enhanced atherosclerotic lesion development of SR-BI KO mice (63.0±9.7*103 μm2 for SR-BI/PLTP dKO (n=8, p<0.05) mice as compared to 117.2±32.4*103 μm2 for SR-BI KO animals (n=5)). Atherosclerosis susceptibility, however, remained elevated as compared to WT animals (1.1±0.1*103 μm2, n=5, p<0.05).
Conclusions: PLTP is essential for the accumulation of the abnormally large HDL particles in SR-BI KO mice and deletion of PLTP reduces the susceptibility to atherosclerosis despite increased levels of pro-atherogenic VLDL particles.
- © 2010 by American Heart Association, Inc.