The nuclear receptor superfamily comprises ligand-activated transcription factors that play important regulatory roles in human and mammalian physiology. We are interested in the role of nuclear receptors in lipid homeostasis. Our long-term goal is to elucidate the regulatory mechanisms controlling lipid homeostasis by nuclear receptors and to identify therapeutic targets or approaches for treatment of hyperlipidemia and coronary heart disease. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays important regulatory roles in maintaining bile acid, lipid and glucose homeostasis. Recent data have shown that activation of FXR inhibits the development of atherosclerosis. Consistent with this latter finding, activation of FXR has been shown to lower plasma cholesterol levels. Hypercholesterolemia is known to be an independent risk factor for atherosclerosis. However, the mechanism by which activation of FXR lowers plasma cholesterol levels and prevents the development of atherosclerosis remains to be established. We have very recently shown that activation of FXR i) lowers plasma cholesterol levels likely via a novel FXR-HNF4a-SR-BI pathway, ii) inhibits intestinal cholesterol absorption and iii) increases reverse cholesterol transport, a process by which extra-hepatic cholesterol is transported back to the liver for secretion to the bile and feces. In this proposal, we will utilize several genetically modified mouse models in combination with molecular, cellular and pharmaceutical approaches to determine the mechanisms by which activation of FXR lowers plasma cholesterol levels, reduces intestinal cholesterol absorption, and increases reverse cholesterol transport. Accomplishing the specific aims in this proposal will provide important insights into the mechanism by which activation of FXR lowers plasma cholesterol levels and prevents the development of atherosclerosis. In addition, completion of the proposed studies may provide novel therapeutic approach(es) for treatment of cardiovascular diseases.

Public Health Relevance

Relevance: Atherosclerosis is the most common cause for coronary heart disease. Completion of the proposed studies will provide important insights into the mechanisms by which activation of FXR lowers plasma cholesterol levels and prevents the development of atherosclerosis. Thus, the studies proposed in this application are highly relevant to cardiovascular diseases and human health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL103227-04
Application #
8598508
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2010-12-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$346,500
Indirect Cost
$121,500
Name
Northeast Ohio Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272
Jadhav, Kavita; Zhang, Yanqiao (2017) Activating transcription factor 3 in immune response and metabolic regulation. Liver Res 1:96-102
You, Min; Jogasuria, Alvin; Lee, Kwangwon et al. (2017) Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1. Curr Mol Pharmacol 10:226-236
Zhang, Guoning; Liu, Shuainan; Tan, Wenjuan et al. (2017) Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists. Eur J Med Chem 129:303-309
Shi, Xin; Zhang, Weihong; Yin, Liya et al. (2017) Vascular precursor cells in tissue injury repair. Transl Res 184:77-100
Xu, Jiesi; Xu, Yang; Xu, Yanyong et al. (2017) Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr -/- mice. Sci Rep 7:17845
Xu, Jiesi; Xu, Yang; Li, Yuanyuan et al. (2016) Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4? and Protects Against Alcohol- and MCD diet-induced Liver Injury. Sci Rep 6:24277
Li, Yuanyuan; Zalzala, Munaf; Jadhav, Kavita et al. (2016) Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice. Hepatology 63:1860-74
Xu, Yang; Li, Fei; Zalzala, Munaf et al. (2016) Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology 64:1072-85
Guarini, Giacinta; Kiyooka, Takahiko; Ohanyan, Vahagn et al. (2016) Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage. Basic Res Cardiol 111:29
Xu, Yang; Zalzala, Munaf; Xu, Jiesi et al. (2015) A metabolic stress-inducible miR-34a-HNF4? pathway regulates lipid and lipoprotein metabolism. Nat Commun 6:7466

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