Seminar: Dr. Marit Westerterp

The role of cholesterol efflux pathways in inflammation and atherosclerosis

Date:
10 April 2015 10:00 hrs. - 11:00 hrs.
Location:
Location see remarks
Title:
The role of cholesterol efflux pathways in inflammation and atherosclerosis
Speaker(s):

Dr. Marit Westerterp, Associate Research Scientist, Dept. of Medicine,Columbia University, USA

Host(s):

Prof. Niels Riksen, Dept. of Internal Medicine, Radboudumc

10-04-2015 10:00:0010-04-2015 11:00:00Europe/AmsterdamThe role of cholesterol efflux pathways in inflammation and atherosclerosis Location see remarksRimlsrimls@radboudumc.nl

Remarks / more information:

undefinedundefinedCardiovascular disease (CVD) is the leading cause of death in the Western world. The majority of CVD cases is caused by atherosclerosis, a condition that develops when an atherosclerotic plaque builds up in the walls of the arteries. High levels of low-density-lipoprotein (LDL)-cholesterol in plasma and high levels of plasma pro-inflammatory cytokines are associated with an elevated risk for CVD. A key process promoting atherosclerosis is foam cell formation, resulting from lipid accumulation in macrophages, inflammatory cells that infiltrate into the vessel wall and promote the formation of the atherosclerotic plaque.
To get rid of their cholesterol, macrophages rely on the cholesterol transporters ATP Binding Cassette Transporters A1 and G1 (ABCA1/G1) that mediate cholesterol efflux to high-density-lipoprotein (HDL) in plasma. The capacity of HDL to promote cholesterol efflux inversely correlates with the incidence of CVD. I found that deficiency of cholesterol efflux pathways mediated by ABCA1/G1 in macrophages increases atherosclerosis in mice. Importantly, this was not only associated with increased foam cell formation but also with increased inflammatory cytokines in plasma and in the atherosclerotic plaque. Inflammation is strongly associated with CVD in humans. My findings in mice were recapitulated in humans heterozygous for a loss of function mutation for ABCA1. On a mechanistic level, I found that cholesterol efflux pathways in mice and humans suppress activation of the inflammasome, a key pathway regulating the production of interleukins promoting inflammation and atherosclerosis. Collectively, my studies indicate that cholesterol efflux pathways suppress inflammation and atherosclerosis in mice and humans. These studies may reveal new therapeutic targets for CVD.  

Key pubications:

Activation of Liver X Receptor Decreases Atherosclerosis in Ldlr−/− Mice in the Absence of ATP-Binding Cassette Transporters A1 and G1 in Myeloid Cells. ArteriosclerThrombVasc Biol. 34:279-284, 2014
Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Macrophages Increases Inflammation and Accelerates Atherosclerosis in Mice. Circ Res. 2013; 112:1456-65.
Regulation of Hematopoietic Stem and Progenitor Cell Mobilization by Cholesterol Efflux Pathways. Cell Stem Cell. 11:195-206, 2012

Location: N. Tulpzaal, route 608 (A-Building) 



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