Cardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol... Show moreCardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol and lipid accumulation. Despite available effective cholesterol lowering medication, considerable risk for recurrent vascular events remains. This residual risk is at least in part explained by high blood lipid levels. The research described in this thesis revealed novel therapeutic strategies that improve lipid metabolism and reduce atherosclerosis development in mice. Inhibition of the endocannabinoid system was found to be an effective strategy, as well as concomitant activation of two incretin hormone receptors, namely those for GIP and GLP1. For combined GIP/GLP1 receptor agonism we additionally showed strongly attenuated hepatic steatosis. We were also able to identify additional targets to attenuate hyperlipidemia by studying the mechanisms underlying the strong day-night rhythm of brown adipose tissue, which is a lipid combusting tissue. In this thesis, I also stress the importance of the choice in animal model when studying lipid-modifying interventions, and describe the development of the software tool RandoMice which can be used to improve the quality of preclinical studies by creating well-balanced experimental groups. Show less
Cardiovascular diseases are still a major concern for the global health. The main underlying pathology of this disease is atherosclerosis which is characterized by the accumulation of lipids and... Show moreCardiovascular diseases are still a major concern for the global health. The main underlying pathology of this disease is atherosclerosis which is characterized by the accumulation of lipids and immune cells in the arterial wall leading to a chronic local inflammation and lesion formation. In this thesis, we aimed to (1) validate the use of zebrafish in cholesterol metabolism and atherosclerosis research, (2) study the role of certain classes of scavenger receptors in lipoprotein uptake and cholesterol-based functions, and (3) validated two immune-based potential targets for atherosclerosis. Show less
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... Show moreThe 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. 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
