Acyl-coenzyme Axholesterol acyltransferase (ACAT) is a membrane-bound enzyme present in a variety of tissues and cells. Using long-chain fatty acyl-coenzyme A and cholesterol as its substrates, ACAT catalyzes the biosynthesis of cholesteryl esters, which comprise part of the neutral lipid cargo packaged into the cores of very low-density lipoproteins and chylomicrons. Under pathophysiological conditions, in cholesterol-loaded macrophages, ACAT converts excess cholesterol into cholesteryl esters. This action reduces the amount of cholesterol available for efflux and converts the macrophages to foam cells, which are the hallmark of early lesions of atherosclerosis. In mammals, two Acat genes exist that encode for two similar but different proteins, ACAT1 and ACAT2. Both enzymes are potential drug targets for pharmaceutical intervention against diseases including atherosclerosis and hyperlipidemia. Recent evidence suggests that ACAT may also be a potential drug target for treating Alzheimer's disease (AD). The long-term objective of this research is to understand the functions of ACAT in vitro, in intact cells, and in animals. For the current proposal, there are two specific aims.
The first aim i s to test certain key features of a biochemical model proposed to explain ACAT1 as an allosteric enzyme.
The second aim i s to determine the pathophysiological role of ACAT in a mouse model for AD. The outcome of the first specific aim will provide the first biochemical model for ACAT;this model will help increase our understanding of the mechanisms of actions of ACAT inhibitors. The outcome of the second specific aim will help determine the pathophysiological role of ACAT in a major neurodegenerative disease. This project aims to build a biochemical model for ACAT1, an enzyme critical to cholesterol metabolism, transport, and storage. Knowledge of how ACAT behaves and is inhibited, as well as what role it may play in the development of Alzheimer's disease in a mouse model, can improve our understanding of the causes and prevention of Alzheimer's disease, a progressive brain disorder that affects an estimated 4.5 million Americans and is becoming increasingly common in the U.S. population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060306-13
Application #
7774362
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (03))
Program Officer
Srinivas, Pothur R
Project Start
1998-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
13
Fiscal Year
2010
Total Cost
$395,546
Indirect Cost
Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Wang, Yong-Jian; Bian, Yan; Luo, Jie et al. (2017) Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat Cell Biol 19:808-819
Yamauchi, Yoshio; Yokoyama, Shinji; Chang, Ta-Yuan (2017) Methods for Monitoring ABCA1-Dependent Sterol Release. Methods Mol Biol 1583:257-273
Yamauchi, Yoshio; Yokoyama, Shinji; Chang, Ta-Yuan (2016) ABCA1-dependent sterol release: sterol molecule specificity and potential membrane domain for HDL biogenesis. J Lipid Res 57:77-88
Huang, Li-Hao; Melton, Elaina M; Li, Haibo et al. (2016) Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion Macrophage Content and Suppresses Atherosclerosis Progression. J Biol Chem 291:6232-44
Yang, Wei; Bai, Yibing; Xiong, Ying et al. (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531:651-5
Yamauchi, Yoshio; Iwamoto, Noriyuki; Rogers, Maximillian A et al. (2015) Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum. J Biol Chem 290:23464-77
Rogers, Maximillian A; Liu, Jay; Song, Bao-Liang et al. (2015) Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators. J Steroid Biochem Mol Biol 151:102-7
Huang, Li-Hao; Nishi, Koji; Li, Song et al. (2014) Acyl-coenzyme A:cholesterol acyltransferase 1 - significance of single-nucleotide polymorphism at residue 526 and the role of Pro347 near the fifth transmembrane domain. FEBS J 281:1773-83
Poirier, Steve; Samami, Samaneh; Mamarbachi, Maya et al. (2014) The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism. J Biol Chem 289:18736-51
Huang, Li-Hao; Gui, Jingang; Artinger, Erika et al. (2013) Acat1 gene ablation in mice increases hematopoietic progenitor cell proliferation in bone marrow and causes leukocytosis. Arterioscler Thromb Vasc Biol 33:2081-7

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