Project Summary Project Summary: 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.