Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

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Project Summary Project Summary: Atherosclerotic cardiovascular diseases (CVD) are the most common causes of death and disability in the developed countries. Atherosclerosis is a chronic inflammatory disease, characterized by lipid accumulation in macrophages of arterial walls. ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) are essential for preventing macrophages from developing into “foam” cells by promoting cholesterol efflux to lipid-free apoA-I or HDL, which subsequently delivers macrophage-derived cholesterol to the liver and intestinal lumen for excretion to the feces. Defective cholesterol efflux leads to formation of foam macrophages, which are activated to contribute to the inflammatory response during atherogenesis. MicroRNAs (miRNAs) are short, non-coding RNAs that bind to the 3'UTR of mRNAs to post-transcriptionally regulate gene expression. Recent studies have documented miRNAs as important regulators of lipid metabolism. We have generated miR-34aApoe double knockout (DKO) mice. Upon fed a Western diet, the DKO mice have a marked reduction in atherosclerotic lesions in both the aorta and aortic root as compared to Apoemice, which is accompanied by unchanged plasma LDL-C or HDL-C levels. Further studies show that miR-34a macrophages have a striking increase in Abca1 and Abcg1 expression and are protective against inflammatory response. Based on our preliminary studies, we hypothesize that inhibition of miR-34a protects against atherosclerosis by increasing macrophage reverse cholesterol transport and inhibiting inflammation. To test this hypothesis, we propose three specific aims to determine whether macrophage miR-34a regulates cholesterol efflux and reverse cholesterol transport, inflammation and atherosclerosis. We will use genetically modified mice and pharmacological manipulations together with state-of-the-art techniques to complete this project. Completion of the proposed studies may uncover a novel role of macrophage miR-34a in cholesterol metabolism, inflammation and atherosclerosis, and may also lead to identification of miR-34a as a novel target for prevention and/or regression of atherosclerosis.