Cardiovascular diseases (CVD) are the leading mortality cause. Its largest underlying issue is atherosclerosis: arterial narrowing due to the buildup of cholesterol, lipids, and immune cells. High... Show moreCardiovascular diseases (CVD) are the leading mortality cause. Its largest underlying issue is atherosclerosis: arterial narrowing due to the buildup of cholesterol, lipids, and immune cells. High blood pressure and cholesterol levels are well-known risk factors. Despite the effectiveness of currently-available medication to improve these factors, a considerable residual risk remains, indicating the importance of other risk factors, such as age and sex. Women have a lower risk of developing CVD than men at a young age, which reverses at older age. CVD are also more common among night shift workers. The research described in this thesis used mouse models to provide new insight in the interplay between sex, age, and disturbances in day and night rhythms in atherosclerosis development, and emphasize the importance of including both men and women in scientific studies. Brown fat is one of the tissues adversely affected by disturbances in day and night rhythms and aging, and the ANGPTL4 protein was identified as an important regulator of brown fat. Inhibiting ANGPTL4 production selectively in liver cells appears a safe and promising therapeutic strategy to combat atherosclerosis. The findings also imply that time-restricted eating could be an effective tool in lowering CVD risk in shift workers. Show less
Cardiovascular diseases (CVD), which are mainly caused by the development of atherosclerosis, are the leading cause of morbidity and mortality in Western Society. Two main risk factors for the... Show moreCardiovascular diseases (CVD), which are mainly caused by the development of atherosclerosis, are the leading cause of morbidity and mortality in Western Society. Two main risk factors for the development of atherosclerosis are hyperlipidemia and inflammation, that cause accumulation of lipids and immune cells, respectively, in the arterial wall. While activation of brown adipose tissue (BAT) is a promising strategy to alleviate hyperlipidemia, reduction of inflammation is also thought to reduce atherosclerosis progression. In this thesis, we aimed to address two key objectives: 1) to identify genetic targets in mice and men that are involved in BAT activity and evaluate their effects on lipoprotein metabolism and atherosclerosis development, and 2) to identify genetic targets in mice that are involved in modulation of the immune system and evaluate their effects on atherosclerosis development. Chapter 1 serves as a general introduction in which hyperlipidemia and inflammation are introduced as the two main causes for atherosclerosis development. More specifically, firstly the physiology and role of BAT in lipoprotein metabolism and atherosclerosis development are explained. Secondly, the contribution of pro- and anti-inflammatory cytokines as well as specific receptors on immune cells in propelling immune responses are explained in the context of atherosclerosis development. 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
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
