ATP binding cassette transporter A1 (ABCA1) effluxes phospholipid (PL) and free cholesterol (FC) from cells, forming nascent high density lipoproteins (nHDL). Because ABCA1 is variably expressed in most cells, we generated hepatocyte-specific ABCA1 KO (HSKO) mice to study the role of hepatocyte ABCA1 in lipid mobilization, transport, and metabolism. We found that hepatocyte ABCA1 regulates the production and catabolism of VLDL, LDL, and HDL, making hepatocyte ABCA1 a key modulator of lipid transport in all three major plasma lipoprotein classes that affect coronary heart disease (CHD) development. In preliminary studies, we found that hepatocyte ABCA1 also regulates hepatic insulin and inflammatory signaling, suggesting the function of hepatocyte ABCA1, while not fully elucidated, is more complex than facilitating bulk cellular cholesterol export and nHDL formation. The goal of this renewal is to determine the role of hepatocyte ABCA1 in liid mobilization and transport in HSKO mice and humans.
In specific aim 1, we will examine the role of hepatocyte ABCA1 expression in hepatic insulin signaling, inflammation, and lipogenesis. Metabolic phenotype, plasma VLDL metabolism, hepatic lipid synthesis, hepatic insulin receptor signaling, and hepatic plasma membrane lipid composition will be determined in chow and high fat-fed WT and HSKO mice.
In specific aim 2, the role of hepatic ABCA1 expression on cholesterol flux from plasma HDL to feces will be examined. We will investigate the plasma decay, hepatic uptake, re-secretion into plasma, and biliary and fecal excretion of HDL FC and CE, relative to apoA-I, in HSKO vs. WT mice.
In specific aim 3, the extent to which dietary polyunsaturated (poly) fat, relative to saturated (sat) and monounsaturated (mono) fat, reduces ABCA1 expression in human liver, intestine and adipose tissue will be explored. Interrelationships among tissue ABCA1 RNA and protein expression, plasma HDL cholesterol concentration, particle number and size, and plasma HDL FC efflux capacity as a function of dietary fat saturation will be determined.
In specific aim 4, we will determine whether rare coding ABCA1 sequence variants unique to African Americans (AA) (absent in European Americans, EA) affect lipid efflux as well as plasma HDL cholesterol concentration, particle number and size, and plasma HDL efflux potential. Associations between these measurements and coronary artery calcified plaque score, a measure of CHD, will be examined.

Public Health Relevance

Coronary heart disease (CHD) remains the number one killer of US citizens. Liver (hepatocyte) ABCA1 expression affects the metabolism of al three major plasma lipoprotein classes (e.g., VLDL, LDL, HDL) that contribute to CHD risk and also affects hepatic insulin signaling. Studies outlined in this project will increase our fundamental knowledge of the causes of CHD and may help lead to improved strategies for prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119962-02
Application #
8705010
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
2013-07-23
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Gromovsky, Anthony D; Schugar, Rebecca C; Brown, Amanda L et al. (2018) ?-5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators. Arterioscler Thromb Vasc Biol 38:218-231
Cuffe, Helen; Liu, Mingxia; Key, Chia-Chi C et al. (2018) Targeted Deletion of Adipocyte Abca1 (ATP-Binding Cassette Transporter A1) Impairs Diet-Induced Obesity. Arterioscler Thromb Vasc Biol 38:733-743
Lee, Sang Gil; Parks, John S; Kang, Hye Won (2017) Quercetin, a functional compound of onion peel, remodels white adipocytes to brown-like adipocytes. J Nutr Biochem 42:62-71
Shewale, Swapnil V; Brown, Amanda L; Bi, Xin et al. (2017) In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice. J Lipid Res 58:236-246
Omar, Ibrahim; Rom, Oren; Aviram, Michael et al. (2017) Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis. Immunology 152:484-493
Key, Chia-Chi C; Liu, Mingxia; Kurtz, C Lisa et al. (2017) Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis. Cell Rep 19:2116-2129
Zamanian-Daryoush, Maryam; Lindner, Daniel J; DiDonato, Joseph A et al. (2017) Myeloid-specific genetic ablation of ATP-binding cassette transporter ABCA1 is protective against cancer. Oncotarget 8:71965-71980
Sajuthi, Satria P; Sharma, Neeraj K; Comeau, Mary E et al. (2017) Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol. Gene 632:50-58
Xian, Xunde; Ding, Yinyuan; Dieckmann, Marco et al. (2017) LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis. Elife 6:
Liu, Yongmei; Reynolds, Lindsay M; Ding, Jingzhong et al. (2017) Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis. Nat Commun 8:393

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