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 #
5R01HL103227-03
Application #
8402620
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
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$366,520
Indirect Cost
$128,520
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
Xu, Jiesi; Li, Yuanyuan; Chen, Wei-Dong et al. (2014) Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis. Hepatology 59:1761-71
Xu, Jiesi; Yin, Liya; Xu, Yang et al. (2014) Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels. PLoS One 9:e109663
Li, Yuanyuan; Jadhav, Kavita; Zhang, Yanqiao (2013) Bile acid receptors in non-alcoholic fatty liver disease. Biochem Pharmacol 86:1517-24
Zhang, Yanqiao; Ge, Xuemei; Heemstra, Lydia A et al. (2012) Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 26:272-80
Ge, Xuemei; Yin, Liya; Ma, Huiyan et al. (2011) Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis. J Lipid Res 52:1561-8