Our long-term goal is to understand molecular mechanisms involved in circadian regulation of lipid metabolism and atherosclerosis and to find out how perturbations in this regulation contribute to atherosclerosis. During the previous study, we showed that dominant negative Clock mutation enhances atherosclerosis by increasing cholesterol absorption in the intestine, augmenting uptake of modified lipoproteins by macrophages, and reducing cholesterol efflux from macrophages. As the central circadian pacemaker and regulator in peripheral tissues, the Clock:Bmal1 heterodimer has been shown to act as a metabolic sensor that directly links circadian rhythms to lipid metabolism and homeostasis. The overall goal of this proposal is to determine the underlying physiological mechanisms through which the transcription factor Bmal1 contributes to atherosclerosis. Here, we hypothesize that Bmal1 is expressed in a circadian manner in macrophages and drives rhythmic expression of genes involved in cholesterol efflux to impact atherogenesis.
The aims are: (1) to investigate the impact of global (Bmal1-/-) or macrophage-specific ablation (M- Bmal1-/-) on the progression of atherosclerosis in Apoe-/- mice through bone marrow transplantation; and (2) to elucidate the physiological mechanisms by which Bmal1 regulates cholesterol efflux and gene expression. These studies will establish whether macrophage-specific Bmal1 plays a critical role in the development of atherosclerosis by regulating cholesterol efflux.
We will identify the physiological as well as molecular mechanisms that are regulated by macrophage Bmal1 and could contribute to atherosclerosis. This proposal specifically addresses the role of macrophage Bmal1 in cholesterol efflux and to determine whether genes involved in RCT, cholesterol efflux from macrophages and atherosclerosis are regulated by Bmal1. We will also identify the cis-elements required for ABCA1 and ABCG1 regulation by Bmal1 and molecular mechanisms that lead to their downregulation through ZNF202.
|Pan, Xiaoyue; Schwartz, Gary J; Hussain, M Mahmood (2018) Oleoylethanolamide differentially regulates glycerolipid synthesis and lipoprotein secretion in intestine and liver. J Lipid Res 59:2349-2359|