hart_vol

Enchen Zhou, MSc

Cardiovascular disease (CVD), mainly caused by atherosclerosis, is the leading cause of death globally. One of the most important risk factors for atherosclerosis is dyslipidemia. Since novel HDL-C-raising strategies recently failed, new targets and approaches on top of statin treatment to lower CVD risk are eagerly awaited. Brown adipose tissue (BAT), a thermogenic organ responsible for maintaining the core temperature in neonates, was previously considered to disappear rapidly upon aging. Only since 2009, functional BAT has been demonstrated in adult humans and BAT contributes substantially to energy metabolism by combusting large amounts of triglycerides and glucose. However, Dong et al. suggested that BAT activation increases plasma cholesterol and atherosclerosis, using mouse models deficient for apoE or the LDL receptor (LDLR). In contrast, we have very recently shown that BAT activation in APOE*3-Leiden.CETP (E3L.CETP) mice, a well-established mouse model for human-like lipoprotein metabolism with an intact apoE-LDLR clearance pathway, can attenuate atherosclerosis. The overall aim of my research is to dissect the mechanism(s) by which activation of BAT attenuates atherosclerosis. We propose that BAT activation stimulates local lipoprotein lipase (LPL)-mediated lipolysis of TG-rich lipoproteins (TRLs), resulting in enhanced generation of cholesterol-rich TRL remnants as well as surface remnants. I will determine the role of lowering plasma (V)LDL versus reverse cholesterol transport in the anti-atherogenic effect of BAT activation in mice and dissect the contribution of (V)LDL versus HDL pathways to cholesterol removal upon BAT activation by using computational modelling in humans.