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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081879-06
Application #
8721935
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Maruvada, Padma
Project Start
2008-07-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Hussain, M Mahmood; Goldberg, Ira J (2018) Human MicroRNA-33b Promotes Atherosclerosis in Apoe-/- Mice. Arterioscler Thromb Vasc Biol 38:2272-2275
Pan, Xiaoyue; Bradfield, Christopher A; Hussain, M Mahmood (2016) Global and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis. Nat Commun 7:13011
Irani, Sara; Pan, Xiaoyue; Peck, Bailey C E et al. (2016) MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice. J Biol Chem 291:18397-409
Khalifeh-Soltani, Amin; Gupta, Deepti; Ha, Arnold et al. (2016) Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity. JCI Insight 1:e87418
Chen, Xueying; Bakillah, Ahmed; Zhou, Liye et al. (2016) Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease. Atherosclerosis 245:12-21
Costabile, Brianna K; Kim, Youn-Kyung; Iqbal, Jahangir et al. (2016) ?-Apo-10'-carotenoids Modulate Placental Microsomal Triglyceride Transfer Protein Expression and Function to Optimize Transport of Intact ?-Carotene to the Embryo. J Biol Chem 291:18525-35
Hussain, M Mahmood; Pan, Xiaoyue (2015) Circadian regulators of intestinal lipid absorption. J Lipid Res 56:761-70
Hussain, M Mahmood; Pan, Xiaoyue (2015) Circadian Regulation of Macronutrient Absorption. J Biol Rhythms 30:459-69
Walsh, Meghan T; Iqbal, Jahangir; Josekutty, Joby et al. (2015) Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal ?-Barrel in Microsomal Triglyceride Transfer Protein Function. Circ Cardiovasc Genet 8:677-87
Irani, Sara; Hussain, M Mahmood (2015) Role of microRNA-30c in lipid metabolism, adipogenesis, cardiac remodeling and cancer. Curr Opin Lipidol 26:139-46

Showing the most recent 10 out of 35 publications