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... Show moreThe 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. Show less
The studies described in this thesis have contributed to the discovery of CETP as a biomarker for the hepatic macrophage content, a hallmark of NASH for which no non-invasive diagnostic method is... Show moreThe studies described in this thesis have contributed to the discovery of CETP as a biomarker for the hepatic macrophage content, a hallmark of NASH for which no non-invasive diagnostic method is currently available, and discovery of novel therapeutic modalities for atherosclerosis and NASH. First of all, we gained more insight into the true cellular origin of CETP (i.e. the liver macrophage), and the mechanisms underlying the CETP-lowering effects of HDL-raising agents (i.e. by reducing the hepatic macrophage content). We extrapolated the association between the reduction of hepatic lipid content and plasma CETP concentration upon lipid-lowering interventions from mice to humans. Furthermore, we demonstrated the role of CETP in discrepant effects of rHDL on VLDL metabolism between mice and humans, and reported a species difference in the central regulation of hepatic VLDL metabolism by NPY between mice and rats, which underscores a general concern in animal research in view of extrapolating findings from specific animal studies to explain observations done in humans. Additionally, we demonstrated that CORT has long-lasting beneficial effects on atherosclerosis development suggesting a possibility for therapeutic application of anti-inflammatory agents in CVD. Finally, we described GLP-1 receptor agonism as a novel strategy to improve lipid metabolism and hepatic inflammation, which may result in novel strategies to treat both atherosclerosis and NASH. Show less
The main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e.... Show moreThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD. Show less
