Our long-term goal is to understand molecular mechanisms involved in the diurnal regulation of plasma lipid concentrations and to find out how perturbations in this regulation contribute to dyslipidemia and atherosclerosis. We observed that plasma triglyceride and cholesterol, mainly those associated with non-HDL apoB-lipoproteins, exhibit diurnal rhythms. During the previous funding cycle, we showed that plasma lipid diurnal rhythms are altered when animals are subject to food entrainment and are not seen in Clock mutant mice. Mechanistic studies revealed that Clock, a critical component of the circadian regulatory loop, controls diurnal regulation of microsomal triglyceride transfer protein (MTP), an essential chaperone for the biosynthesis of apoB-containing triglyceride-rich lipoproteins, involving SHP. This regulatory process suppresses MTP expression and lowers plasma triglycerides at the onset of light in mice. When circadian control is impaired mice develop sustained hyperlipidemia because this regulatory mechanism becomes inoperative. Hence, we hypothesize that circadian mechanisms protect against hyperlipidemia and atherosclerosis. Besides Clock, the positive loop of circadian regulation requires Bmal1.
The aim of this proposal is to define the role of Bmal1 in the development of hyperlipidemia and atherosclerosis and to uncover molecular, biochemical, and physiological mechanisms that control plasma lipid and atherosclerosis. Our approach will be to ablate Bmal1 expression globally or in tissue-specific manner and then to compare various physiological, biochemical, and molecular aspects with their wild type siblings.
Our first aim i s to elucidate the role of Bmal1 in diurnal and food entrained regulation of plasma lipids and lipoproteins.
The second aim i s to ascertain the contribution of hepatic and intestinal Bmal1 in the regulation of plasma lipids/lipoproteins.
The third aim i s to recognize the role of Bmal1 in the progression of atherosclerosis. Bmal1-/- /Ldlr-/- and Bmal1-/-/Apoe-/- mice on C57BL/6J background will be fed ad libitum chow or western diet and development of atherosclerosis will be documented. Additionally, we will evaluate the effect of intestinal and hepatic Bmal1 ablation on atherosclerosis. We expect to demonstrate that Bmal1 is vital in maintaining plasma lipid and lipoprotein homeostasis, and in the prevention of atherosclerosis. The outcomes from these studies will impact two fields of biology; lipid metabolism and circadian regulation. Novel understanding about the circadian regulation of lipid metabolism will be garnered.
These studies are to determine whether genes involved in circadian regulation affect plasma lipid levels and atherosclerosis. This proposal specifically addresses the role of Bmal1 in the diurnal regulation of plasma lipids and development of atherosclerosis. The proposed studies will also provide new information about the role of Bmal1 in food entrained regulation of plasma lipids.
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