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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Liu, Lijuan
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Northeast Ohio Medical University
Other Basic Sciences
Schools of Medicine
United States
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Xu, Jiesi; Xu, Yang; Li, Yuanyuan et al. (2016) Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury. Sci Rep 6:24277
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
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
You, Min; Jogasuria, Alvin; Lee, Kwangwon et al. (2015) Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emerging Role of Lipin-1. Curr Mol Pharmacol :
Xu, Yang; Zalzala, Munaf; Xu, Jiesi et al. (2015) A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism. Nat Commun 6:7466
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

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