CETP and Inflammation in lipid metabolism and atherosclerosis

The studies described in this thesis show that inflammation and CETP are both important factors in lipid metabolism and atherosclerosis. In the first part of this thesis we showed that high dietary cholesterol can induce hepatic inflammation via disturbed cholesterol homeostasis and ER stress, revealing new targets for the treatment of metabolic inflammation. Next, we demonstrated that intervention in both systemic and vascular inflammation can reduce atherosclerosis progression and/ or induce regression, highlighting the importance of developing drugs targeting the inflammatory component of atherosclerotic disease. In the second part of this thesis we showed that CETP inhibition per se may be anti-atherogenic, but that combination therapy of the CETP inhibitor torcetrapib with atorvastatin may have obscured its atheroprotective effect. Furthermore, we showed that the VLDL-increasing effect of CETP largely explains its atherogenic effect, at least in APOE*3-Leiden.CETP mice, and that CETP inhibition may negatively affect lesion stability. Our data suggest that CETP inhibition may not be the most optimal strategy to increase HDL-C levels and thereby reduce atherosclerosis. We anticipate that strategies improving HDL functionality, rather than raising the HDL level, are more likely to effectively reduce CVD.