This project is focused on nuclear receptor regulation of metabolic and inflammatory gene expression and the impact of nuclear receptor signaling on cardiovascular disease. Work from this project over the past ten years has established that LXRs function as transcriptional regulators of cholesterol metabolism and modulators of immunity and inflammation. Studies in the current grant period have revealed novel mechanisms whereby cholesterol metabolism may impact immune functions of macrophages. We identified new LXR target genes (arginase II and Mertk) that regulate macrophage inflammatory and phagocytic capacity. In addition, we provided in vivo evidence that the LXR signaling pathway is an important determinant of atherosclerosis susceptibility and immune tolerance. Finally, we identified a novel mechanism whereby LXR activation regulates cholesterol uptake through the LDL receptor pathway. We identified an E3 ubiquitin ligase termed Idol that targets the LDLR for degradation in response to LXR activation. In the next funding period we will extend this work by investigating the mechanism and physiologic function of the LXR-Idol-LDLR axis in cellular cholesterol uptake. We will also utilize mouse models to determine the function of Idol in systemic lipid metabolism and its impact on atherosclerosis. These studies are expected to provide insight into novel mechanisms by which LXR and Idol regulate cholesterol homeostasis and atherosclerosis and may identify additional targets for intervention in cardiovascular disease.
Specific Aim 1 is to use in vitro models to define the function of the LXR-Idol-LDLR axis in cellular cholesterol homeostasis. We will utilize gain and loss of function systems to determine the impact of Idol expression on cholesterol uptake, metabolic gene expression, and potential crosstalk with the SREBP signaling pathway. We will also use site-directed mutagenesis and functional assays to define the regions of Idol and LDLR important for Idol-LDLR recognition and ubiquitination.
Specific Aim 2 is to use in vivo models to define the function of the LXR-Idol-LDLR axis in systemic lipid metabolism. We have generated transgenic animals that express Idol from the liver-specific albumin promoter. We have also generated mice carrying a global deletion in the Idol gene. We will use these models to examine the ability of Idol to affect plasma cholesterol levels, as well as its influence on hepatic and peripheral cholesterol metabolism.
Specific Aim 3 is to determine the impact of Idol on macrophage lipid homeostasis and the development of atherosclerosis. We will use gain- and loss-of-function approaches to test the hypothesis that the LXR-Idol pathway is a physiologic limiter of macrophage cholesterol accumulation. To test the relevance of the macrophage Idol pathway for atherogenesis, we will analyze lesion formation in LDLR-/- mice transplanted with WT or Idol-/- bone marrow. We will also generate and analyze lesion formation in Idol-/- human apoBTg mice.

Public Health Relevance

A detailed understanding of nuclear receptor function in macrophages and other cells is expected to provide insight into basic molecular mechanisms controlling lipid metabolism and inflammation as well as the pathobiology of atherosclerosis. Our identification in the current funding period of Idol, a specific mediator of LDLR degradation, provides interesting new insight into the LDLR pathway, known to be a major contributor to human cardiovascular disease risk. Ultimately, the studies proposed in this application may form the basis for the development of new diagnostic and therapeutic approaches to cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066088-13
Application #
8290228
Study Section
Special Emphasis Panel (ZRG1-VH-D (03))
Program Officer
Srinivas, Pothur R
Project Start
2001-02-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$338,027
Indirect Cost
$115,277
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tian, Xiao Yu; Ganeshan, Kirthana; Hong, Cynthia et al. (2016) Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance. Cell Metab 23:165-78
Ito, Ayaka; Hong, Cynthia; Oka, Kazuhiro et al. (2016) Cholesterol Accumulation in CD11c(+) Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease. Immunity 45:1311-1326
Sallam, Tamer; Jones, Marius C; Gilliland, Thomas et al. (2016) Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature 534:124-8
Choi, Jinkuk; Gao, Jie; Kim, Jaekwang et al. (2015) The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis. Sci Transl Med 7:314ra184
Ito, Ayaka; Hong, Cynthia; Rong, Xin et al. (2015) LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. Elife 4:e08009
Lee, Stephen D; Tontonoz, Peter (2015) Liver X receptors at the intersection of lipid metabolism and atherogenesis. Atherosclerosis 242:29-36
Warrier, Manya; Shih, Diana M; Burrows, Amy C et al. (2015) The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance. Cell Rep :
Hong, Cynthia; Tontonoz, Peter (2014) Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov 13:433-44
Calkin, Anna C; Lee, Stephen D; Kim, Jason et al. (2014) Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice. Circ Res 115:442-9
Hong, Cynthia; Marshall, Stephanie M; McDaniel, Allison L et al. (2014) The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab 20:910-8

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