The liver X receptors LXR (NR1H3) and LXR (NR1H2), members of the nuclear hormone receptor superfamily of transcription factors, have been identified as important regulators of cholesterol homeostasis. Treatment with LXR agonists promotes the efflux of cholesterol from cells, a process termed reverse cholesterol transport (RCT), by increasing expression of the genes encoding the ATP binding cassette transporters ABCA1 and ABCG1 and the apolipoprotein apoE. The uptake of oxidized cholesterol by macrophages plays a critical role in the development and pathogenesis of atherosclerosis and it has been suggested that enhancing RCT in these cells would retard disease progression. Importantly, treatment with LXR agonists reduces atherosclerosis in animal models of cardiovascular disease at least in part by up- regulation of RCT. Not surprisingly there are intense efforts underway in academic and in pharmaceutical laboratories to identify LXR ligands, however, a major limitation associated with first generation compounds is their propensity to increase plasma lipid levels. A genetic analysis of the individual anti-atherogenic potential of each LXR subtype uncovered a critical therapeutic role for LXR. These studies also demonstrated that activation of LXR in macrophages as well as at a novel non-macrophage site(s) is required for full therapeutic potential. The main goal of this proposal is to define the therapeutic potential of LXR in atherosclerosis, elucidate its underlying mechanism and identify novel therapeutic sites of action. Functional analysis of the two LXR subtypes indicates that LXR is stronger activator of the genes involved in RCT while LXR is a stronger repressor of gene expression. Thus in the absence of LXR RCT is not sufficiently induced when cholesterol levels are high leading to intracellular cholesterol accumulation and an increased risk for atherosclerosis. One goal of the proposed research is to use molecular approaches to identify the trans-acting factors that confer subtype specific differences in anti-atherogenic activity. Molecular and cellular characterization of these trans-acting factors should provide unique entry points for the discovery of novel treatments for atherosclerosis. Additionally, the liver plays a major role in the control of cholesterol homeostasis by serving as the site of lipoprotein production, by synthesizing and secreting the enzymes that remodel lipoproteins, and as the site of lipoprotein-borne sterol clearance. A second goal of the proposed research will be utilize cellular and animal models to define the liver as a novel site of LXR-dependent anti- atherogenic activity. The results of these studies should assist in the identification LXR ligands with minimal side effects and improved anti-atherogenic activity.

Public Health Relevance

Cardiovascular disease is the leading killer of adults in the Western world and statistics from the American Heart Association indicate that more than 50% of adults living in the United States have cholesterol levels that put them at risk for atherosclerosis. The liver X receptors (LXRs) are important regulators of cholesterol homeostasis throughout the body and the experimental approaches described in this application will define the factors controlling LXR activity and will describe important sites of LXR action. The results of these studies should provide innovative strategies for the development of therapies for the treatment of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096864-03
Application #
8230549
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2010-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$381,150
Indirect Cost
$133,650
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Ignatova, Irena D; Schulman, Ira G (2014) Liver X receptors and atherosclerosis: it is not all cholesterol. Arterioscler Thromb Vasc Biol 34:242-3
Breevoort, Sarah R; Angdisen, Jerry; Schulman, Ira G (2014) Macrophage-independent regulation of reverse cholesterol transport by liver X receptors. Arterioscler Thromb Vasc Biol 34:1650-60
Leitinger, Norbert; Schulman, Ira G (2013) Phenotypic polarization of macrophages in atherosclerosis. Arterioscler Thromb Vasc Biol 33:1120-6
Ignatova, Irena D; Angdisen, Jerry; Moran, Erin et al. (2013) Differential regulation of gene expression by LXRs in response to macrophage cholesterol loading. Mol Endocrinol 27:1036-47
Zhang, Yuan; Breevoort, Sarah R; Angdisen, Jerry et al. (2012) Liver LXR* expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. J Clin Invest 122:1688-99
Schulman, Ira G (2010) Nuclear receptors as drug targets for metabolic disease. Adv Drug Deliv Rev 62:1307-15