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
Cardiometabolic diseases including atherosclerotic cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are the leading cause of preventable death worldwide.... Show moreCardiometabolic diseases including atherosclerotic cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are the leading cause of preventable death worldwide. Hypercholesterolemia and inflammation are common major risk factors for atherosclerotic CVD as well as NAFLD. The studies described in this thesis aimed to get insight in strategies how to further improve cholesterol metabolism and inflammation, by exploring the therapeutic potential of brown fat activation and transcription factors involved in both processes. The results described in this thesis have increased our insight into regulation of cholesterol metabolism and inflammation by brown fat and nuclear receptors, respectively, and provided promising leads for innovative treatment of cardiometabolic diseases including brown fat activation, Δ24-dehydrocholesterol reductase inhibition, and farnesoid X receptor activation. Show less
Cholesterol influences many pathways, including serving as precursor for adrenal steroidogenesis. Imbalance of cholesterol levels has been implicated in several diseases including cardiovascular... Show moreCholesterol influences many pathways, including serving as precursor for adrenal steroidogenesis. Imbalance of cholesterol levels has been implicated in several diseases including cardiovascular diseases and its underlying pathology, atherosclerosis. Here we concentrate on the role of a) lipid metabolism, especially high-density lipoprotein (HDL), in the development and regression of atherosclerosis and b) apolipoprotein E in adrenal glucocorticoid (GC) synthesis. We showed the importance of HDL size and functionality on atherosclerotic lesion formation in scavenger receptor-BI (SR-BI) knockout mice. Normalisation of the enlarged HDL particle size phenotype in these mice, trough depletion of phospholipid transfer protein, decreased atherosclerotic susceptibility and, contrary, development of a metabolic syndrome like phenotype. Furthermore, we studied the importance of HDL during regression of existing lesions in hypercholesterolemic apolipoprotein-E (ApoE) knockout mice. Normalizing the hypercholesterolemia resulted in regression of lesions and additional HDL depletion impaired the regression.The specific contribution of lipoprotein fractions to steroidogenesis is unknown. We lowered the (very) large-density lipoprotein fraction in ApoE-KO mice, resulting in a decreased GC output. ApoE is also produced within the adrenal where its local role is unclear. By transplanting an ApoE KO adrenal into an adrenalectomized wild-type mouse we revealed that local ApoE does not impact GC synthesis. Show less
The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
The thesis discussed several strategies that may contribute to further CVD risk reduction in the future. We described two novel lipid-lowering strategies, we unraveled (part of) the etiology of the... Show moreThe thesis discussed several strategies that may contribute to further CVD risk reduction in the future. We described two novel lipid-lowering strategies, we unraveled (part of) the etiology of the cardiovascular safety issues of TKIs that are used for the treatment of CML, and we investigated the dose effects of PFOA on lipoprotein metabolism. Looking forward, we developed a novel mouse model that can be used for the study of diabetic macrovascular complications, and we evaluated the potential of OSM as novel target in CVD. Show less
Adrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the... Show moreAdrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the development of atherosclerotic cardiovascular disease. Here we review preclinical and clinical findings regarding the relation between changes in plasma glucocorticoid levels and the atherosclerosis extent. It appears that, although the altered glucocorticoid function can in most cases be restored in the different patient groups, current therapies do not necessarily reverse the associated risk for atherosclerotic cardiovascular disease. In our opinion much attention should therefore be given to the development of a Cushing's disease mouse model that can (1) effectively replicate the effect of hypercortisolemia on atherosclerosis outcome observed in humans and (2) be used to investigate, in a preclinical setting, the relative impact on atherosclerosis susceptibility of already available (e.g. metyrapone) and potentially novel (i.e. SR-BI activity modulators) therapeutic agents that target the adrenal glucocorticoid output. Show less
Although studies in mice have suggested that lesion regression is feasible, the underlying mechanisms remain largely unknown. Here we determined the impact of high-density lipoprotein (HDL) on... Show moreAlthough studies in mice have suggested that lesion regression is feasible, the underlying mechanisms remain largely unknown. Here we determined the impact of high-density lipoprotein (HDL) on atherosclerosis regression outcome.\nAtherosclerotic lesion dynamics were studied upon bone marrow transplantation-mediated re-introduction of apolipoprotein E (Apoe) in Apoe knockout mice. Probucol was used to pharmacologically deplete HDL.\n for controls: p < 0.05).\nWe have shown that probucol-induced HDL deficiency impairs the ability of established lesions to regress in response to reversal of the genetic hypercholesterolemia in Apoe knockout mice. Our studies thus highlight a crucial role for HDL in the process of atherosclerosis regression. 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
Atherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i... Show moreAtherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i.e. elevated plasma levels apo-B-containing lipoproteins) is a major causative factor in atherogenesis. It is equally clear that atherogenesis has an inflammatory component which is thought to drive the progression of the disease. However, while the lipid component in atherosclerosis development is relatively well-understood, the origin and exact contribution of the inflammatory component remains largely unknown. The aim of this thesis is to further define and delineate the contribution of the inflammatory component to the atherosclerotic process and to elucidate the link between cholesterol and inflammation in atherosclerotic lesion formation and progression. The studies of this thesis show that, besides plasma cholesterol, inflammation contributes to a substantial extent to atherogenesis. Intervention strategies directed at lowering apoB-containing lipoproteins and reducing inflammation may therefore be more effective than current lipid-lowering strategies. Direct experimental evidence for this assumption mainly comes from animal experiments as described in this thesis. Human intervention studies are necessary to evaluate whether these findings can also be translated to the human situation. 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
