Novel mechanistic insight in cholesteryl ester transfer protein production and pharmacological inhibition

The aim of this thesis was to better understand the cellular origin of cholesteryl ester transfer protein (CETP) and to investigate the effects of the CETP inhibitor anacetrapib on the development of atherosclerosis. First, we investigated the specific characteristics of hepatic macrophages that express CETP. Our data clearly indicated that in the liver, CETP is exclusively expressed by F4/80+Ly6C-Clec4f+Vsig4+ macrophages that represent resident, rather than immature macrophages. Next, we showed that the HDL response to the inflammatory stimulus lipopolysaccharide is mediated by hepatic macrophages via down regulation of CETP expression in the liver that causes an increase in the level of HDL-C. In the second part of this thesis, we examined the effects and mechanism of pharmacological inhibition of CETP by anacetrapib on the development of atherosclerosis. We concluded that anacetrapib mainly decreases atherosclerotic lesion development via a reduction of non-HDL-C. Finally, we concluded that anacetrapib reduces (V)LDL-C by increasing hepatic remnant clearance via two mechanisms: 1) inhibition of CETP activity, resulting in remodelled VLDL particles that are more susceptible to hepatic clearance, and 2) a CETP-independent reduction in plasma PCSK9 level that has the potential to increase LDL receptor-mediated hepatic remnant clearance.