Cardiovascular disease (CVD) is a major cause of mortality and morbidity in the Western world. CVD is mainly caused by atherosclerosis, for which dyslipidemia, characterized by high a plasma level... Show moreCardiovascular disease (CVD) is a major cause of mortality and morbidity in the Western world. CVD is mainly caused by atherosclerosis, for which dyslipidemia, characterized by high a plasma level of (very) low density lipoprotein ((V)LDL) and a low plasma level of high density lipoprotein (HDL), is a major risk factor. To reduce the risk to develop CVD, drugs aimed at correcting dyslipidemia by lowering (V)LDL are currently the first choice of treatment. Albeit that these drugs lower (V)LDL-C very efficiently (up to ~40%), and generally result in a slight increase in HDL-C, they only prevent a fraction of all cardiovascular events (~30%). Therefore new therapeutic strategies to reduce cardiovascular events more efficiently are necessary. Since HDL is has been attributed multiple protective effects in atherosclerosis by its role in reverse cholesterol transport and its anti-inflammatory and anti-oxidative properties, HDL-raising therapy is currently considered as a promising strategy to further reduce CVD risk. In this thesis, the mechanisms underlying the HDL-raising effects of the classical lipid-lowering drugs fenofibrate, atorvastatin and niacin were elucidated. Furthermore, the effects of potential novel HDL-raising strategies, including torcetrapib, PXR agonism and apoCI, on HDL metabolism were addressed. For these studies, we used the APOE*3-Leiden.CETP (E3L.CETP) transgenic mouse, a valuable model for human-like lipoprotein metabolism Show less
This thesis contributes to a better understanding of the roles of apoCI, LPL, and CETP in lipoprotein metabolism. Our data illustrate that the activity of LPL, and thereby the level of plasma TG,... Show moreThis thesis contributes to a better understanding of the roles of apoCI, LPL, and CETP in lipoprotein metabolism. Our data illustrate that the activity of LPL, and thereby the level of plasma TG, is crucially determined by the relative abundance of apolipoproteins. In addition, we showed that LPL is an important determinant in remnant-particle clearance in the absence of the three main apoE-recognizing receptors. Finally, we demonstrated that CETP presents a pro-atherogenic factor in mice resembling a human lipid distribution over lipoproteins and that atorvastatin and fenofibrate treatment influence HDL-metabolism via inhibition of CETP, which may thus add to their therapeutic benefit. Since there were initial concerns that inhibition of CETP would reduce the flux of cholesteryl esters from the periphery back to the liver, thereby possibly increasing the risk for atherosclerosis, it is of interest that we found that fenofibrate-mediated inhibition of CETP did not hamper the total flux of HDL-cholesteryl esters. This holds promise for therapies based on CETP inhibition. Show less
