Atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid... Show moreAtherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid accumulation in the vascular wall and liver, respectively. In the body, lipids are transported between organs within lipoproteins, and thus disordered lipoprotein metabolism is closely associated with ASCVD and MASLD development. Active brown adipose tissue (BAT) combusts lipids to produce heat, and BAT activation is therefore considered a potential strategy to improve lipoprotein metabolism. In this thesis, I describe a new method of monitoring lipoprotein metabolism and BAT activity by PET-CT scan. To this end, a newly developed 18F-labeled lipid tracer was incorporated in optimized lipoprotein-like particles, and appeared to outperform 18F-deoxyglucose in tracing activated BAT. The results presented in this thesis also further confirm the usefulness of the APOE*3-Leiden.CETP mouse model for studying therapeutic interventions to improve lipoprotein metabolism. Using this translational model, I demonstrated that exercise at the end of the active phase and combined glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide receptor agonism, a strategy for treating diabetes and obesity in the clinic, are promising ways to combat both ASCVD and MASLD. Show less
Panhuis, W.I.H.; Schönke, M.; Modder, M.; Tom, H.E.; Lalai, R.A.; Pronk, A.C.M.; ... ; Kooijmana, S. 2023
BackgroundCircadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift... Show moreBackgroundCircadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift work has been associated with elevated risk for atherosclerotic cardiovascular disease (asCVD) in humans, but evidence for the effectiveness of prevention strategies is lacking.MethodsHere, we applied time-restricted feeding (TRF) as a strategy to counteract atherosclerosis development during CD in female APOE∗3-Leiden.CETP mice, a well-established model for humanized lipoprotein metabolism. Control groups were subjected to a fixed 12:12 h light–dark cycle, while CD groups were subjected to 6-h phase advancement every 3 days. Groups had either ad libitum (AL) access to food or were subjected to TRF with restricted food access to the dark phase.FindingsTRF did not prevent the increase in the relative abundance of circulating inflammatory monocytes and elevation of (postprandial) plasma triglycerides during CD. Nonetheless, TRF reduced atherosclerotic lesion size and prevented an elevation in macrophage content of atherosclerotic lesions during CD, while it increased the relative abundance of anti-inflammatory monocytes, prevented activation of T cells, and lowered plasma total cholesterol levels and markers of hepatic cholesterol synthesis. These effects were independent of total food intake.InterpretationWe propose that time restricted eating could be a promising strategy for the primary prevention of asCVD risk in shift workers, which warrants future study in humans.FundingThis work was funded by the Novo Nordisk Foundation, the Netherlands Ministry of Social Affairs and Employment, Amsterdam Cardiovascular Sciences, and the Dutch Heart Foundation. Show less
Eenige, R. van; Ying, Z.X.; Tramper, N.; Wiebing, V.; Siraj, Z.; Boer, J.F. de; ... ; Kooijman, S. 2023
Background and aims: Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in... Show moreBackground and aims: Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in terms of glycemic control and lowering body weight in individuals with obesity and with or without type 2 diabetes mellitus. As both GIPR and GLP1R signaling have also been implicated in improving inflammatory responses and lipid handling, two crucial players in atherosclerosis development, here we aimed to investigate the effects of combined GIPR/GLP1R agonism in APOE*3-Leiden.CETP mice, a well-established mouse model for human-like lipoprotein metabolism and atherosclerosis development. Methods: Female APOE*3-Leiden.CETP mice were fed a Western-type diet (containing 16% fat and 0.15% cholesterol) to induce dyslipidemia, and received subcutaneous injections with either vehicle, a GIPR agonist (GIPFA-085), a GLP1R agonist (GLP-140) or both agonists. In the aortic root area, atherosclerosis development was assessed. Results: Combined GIPR/GLP1R agonism attenuated the development of severe atherosclerotic lesions, while single treatments only showed non-significant improvements. Mechanistically, combined GIPR/GLP1R agonism decreased markers of systemic low-grade inflammation. In addition, combined GIPR/GLP1R agonism markedly lowered plasma triglyceride (TG) levels as explained by reduced hepatic very-low-density lipoprotein (VLDL)-TG production as well as increased TG-derived fatty acid uptake by brown and white adipose tissue which was coupled to enhanced hepatic uptake of core VLDL remnants. Conclusions: Combined GIPR/GLP1R agonism attenuates atherosclerosis severity by diminishing inflammation and increasing VLDL turnover. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to lower cardiometabolic risk in humans. Show less
Aims: Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the... Show moreAims: Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive. Methods and results: Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to up-regulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity, and increased atherosclerotic plaque stability index. Conclusion: FGF21 improves hypercholesterolaemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease. 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
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
This PhD thesis contains the following chapters. The first part, containing chapter 2 and 3 mainly concerns model development. Chapter 2 describes the development of a mathematical modeling... Show moreThis PhD thesis contains the following chapters. The first part, containing chapter 2 and 3 mainly concerns model development. Chapter 2 describes the development of a mathematical modeling framework within which different diagnostic models based on lipoprotein profiles can be developed, and a first validation of a model in this framework using data from a stable__isotope flux study (78). Chapter 3 describes a further development of the model, and the development of a new lipoprotein model__based candidate diagnostic and its validation using a range of stable__isotope flux studies. The second part, containing chapter 4, 5, and 6, concerns model applications. Chapter 4 contains the first application of the model__based candidate diagnostic using HPLC__measured lipoprotein profiles, in the context of a nutritional intervention study conducted at TNO. Chapter 5 contains an exploration of lipoprotein profile data from a population study (the GOLDN study), and examines how subgroups of patients, identified via K__means clustering based on lipoprotein profiles, differ in their lipid response to a fenofibrate intervention. It also examines how the model__based candidate diagnostic behaves in these subgroups. Chapter 6 contains the study that shows that lipoprotein metabolism indicators may have predictive value for cardiovascular risk on top of classical risk markers. Chapter 7 contains a methodological reflection on the development of computational models for clinical diagnostic use based on clinical chemistry data. Finally, chapter 8 contains a general discussion of the research presented in this PhD thesis and suggestions for further research Show less
Obesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public... Show moreObesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public health. Excessive energy intake is an important cause of obesity since excess energy is primarily stored as fat. The stored fat is mobilized again during fasting in the form of fatty acids (FA). These FA are re-esterified in the liver in triglycerides (TG) that are secreted in VLDL particles to deliver FA to peripheral tissues where they can be used for energy. One of the current views of the cause of diseases related to obesity is the (mis)handling of TG derived FA. Therefore it is important to understand pathways involved in the uptake, distribution, oxidation and storage of TG. In this thesis we have evaluated the effect of different interventions on VLDL-TG metabolism to gain a better understanding of its complex regulation. For these studies we used APOE*3-Leiden (E3L) and E3L.CETP transgenic mice that have a human-like lipoprotein metabolism and respond to lipid-modifying drugs in a ways similar to humans. 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
