Atherosclerotic cardiovascular disease (CVD) is the most common cause of mortality and morbidity in the Western world. Cholesterol accumulation in arterial macrophages and inflammation of the artery wall both contribute to development of CVD. There is an inverse relationship between plasma high-density (HDL) levels and cardiovascular risk, implying that factors associated with HDL metabolism are cardioprotective. HDL protects against CVD by several mechanisms that remove cholesterol from arterial cells and suppress inflammation. A major cardioprotective factor associated with HDL metabolism is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that exports cholesterol and phospholipids from cells to lipid-depleted HDL apolipoproteins, such as apoA-I. We found that ABCA1 also functions as an anti-inflammatory signaling receptor through activation of a JAK2/STAT3 pathway, which is independent of cholesterol export activity. Thus, macrophage ABCA1 provides a direct biochemical link between the cardioprotective effects of reverse cholesterol transport and suppressed inflammation. These observations indicate that ABCA1 is an attractive therapeutic target for treating the two major underlying mechanisms that cause CVD. The goal of this project is to determine the cellular processes involved in the cholesterol export and anti-inflammatory activities of ABCA1 and to assess their cardioprotective roles in vivo. We propose to use mutagenesis, biochemical, and mass spectrometric techniques to evaluate the effects of apolipoprotein-ABCA1 interactions on cholesterol export and inflammatory cytokine production and to characterize cellular mechanisms involved. We also propose to use atherosclerosis-susceptible mouse models to determine how these anti-inflammatory and cholesterol export functions of ABCA1 contribute to atherosclerosis in whole animals. This information will define possible sites of impairment of these pathways that may be clinically relevant and uncover potential targets for therapeutic interventions for preventing CVD.

Public Health Relevance

HDL protects against heart disease by removing artery-blocking cholesterol from arterial cells and inhibiting inflammation. A cell protein called ABCA1 can perform both of these heart-protecting functions. This research will investigate the cell pathways involved in the cholesterol removal and anti-inflammatory actions of ABCA1 and determine if these pathways protect against heart disease in animals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055362-13
Application #
7759216
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
13
Fiscal Year
2010
Total Cost
$415,000
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tang, Chongren; Liu, Yuhua; Yang, Wendy et al. (2016) Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice. J Lipid Res 57:100-8
Tang, Chongren; Houston, Barbara A; Storey, Carl et al. (2016) Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages. J Lipid Res 57:848-57
Rider, T; LeBoeuf, R C; Tso, Patrick et al. (2016) The Use of Kits in the Analysis of Tissue Lipids Requires Validation. Lipids 51:497-504
Wei, Hao; Tarling, Elizabeth J; McMillen, Timothy S et al. (2015) ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction. J Lipid Res 56:2337-47
Lee, Jung-Ting; Pamir, Nathalie; Liu, Ning-Chun et al. (2014) Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase. Endocrinology 155:3409-20
Spiezio, Sabrina H; Amon, Lynn M; McMillen, Timothy S et al. (2014) Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice. Mamm Genome 25:549-63
Cheng, Andrew M; Handa, Priya; Tateya, Sanshiro et al. (2012) Apolipoprotein A-I attenuates palmitate-mediated NF-?B activation by reducing Toll-like receptor-4 recruitment into lipid rafts. PLoS One 7:e33917
Rubinow, Katya B; Tang, Chongren; Hoofnagle, Andrew N et al. (2012) Acute sex steroid withdrawal increases cholesterol efflux capacity and HDL-associated clusterin in men. Steroids 77:454-60
Edgel, Kimberly A; McMillen, Timothy S; Wei, Hao et al. (2012) Obesity and weight loss result in increased adipose tissue ABCG1 expression in db/db mice. Biochim Biophys Acta 1821:425-34
Liu, Yuhua; Tang, Chongren (2012) Regulation of ABCA1 functions by signaling pathways. Biochim Biophys Acta 1821:522-9

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