Hypercholesterolemia is an independent risk factor for atherosclerosis, the most common cause for coronary artery disease (CAD). Numerous preclinical and clinical studies have demonstrated that lowering plasma LDL cholesterol (LDL-C) levels and/or enhancing HDL functionality are effective approaches to lower the incidence of CAD. The liver plays a central role in maintaining bile acid (BA), triglyceride (TG) and cholesterol homeostasis by coordinating regulation of a number of genes and signaling pathways. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP response element-binding (ATF/CREB) family of transcription factors, and is shown to inhibit inflammatory response in macrophages. So far, the role of hepatic ATF3 in regulating cholesterol or bile acid metabolism is completely unknown. Our preliminary studies have shown that hepatic ATF3 regulates plasma cholesterol levels likely by coordinating plasma cholesterol uptake by the liver and BA metabolism. As a result, hepatic ATF3 may regulate the development or regression of atherosclerosis. In this project, we will use both gain- and loss-of-function approaches to test this hypothesis. Our studies may help identify hepatic ATF3 as a novel regulator of cholesterol and bile acid metabolism and atherosclerosis.

Public Health Relevance

Relevance: Atherosclerosis is the most common form of cardiovascular disease. Completion of the proposed studies will help determine the role of hepatic ATF3 in the development or regression of atherosclerosis, and may lead to identification of hepatic ATF3 as a novel target for treatment of atherosclerosis. Thus, the studies proposed in this application are highly relevant to human health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL142086-01
Application #
9531867
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2018-07-01
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
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