Human apolipoprotein (Apo) E includes three common isoforms known as ApoE2, ApoE3 and ApoE4. ApoE3 is considered to be the normal isoform, while ApoE2 and ApoE4 are dysfunctional. Individuals carrying defective isoforms of ApoE develop hypercholesterolemia and atherosclerosis. Similarly, ApoE null knockout (ApoE-/-) mice suffer from hypercholesterolemia and atherosclerosis resembling the human disease. The hypercholesterolemia in ApoE-deficient patients and mouse models results mainly from an increased plasma level of remnant lipoproteins that contain ApoB48. Previous studies from our laboratory demonstrate that the remnant lipoproteins obtained from ApoE-/- mice is able to transform macrophages into foam cells, and that foam cell formation induced by ApoE-free remnant lipoproteins coincides with an enhanced phosphorylation of eukaryotic translation initiation factor 21 (eIF-21), which is a cellular event related to endoplasmic reticulum (ER) stress. We also observed that inhibition of eIF-21 phosphorylation attenuated ApoE-free remnant lipoprotein-induced foam cell formation. Moreover, we observed that mouse remnant lipoproteins enriched with defective isofoms of human ApoE, especially those enriched with ApoE4, induced cholesterol accumulation and eIF-21 phosphorylation in macrophages. It is highly likely that in the absence of, or deficiency in, ApoE, interaction of remnant lipoproteins with macrophages activates ER stress-related signaling pathways, which in turn regulate the expression of genes whose encoded products contribute to foam cell formation. In this project, we will test a hypothesis that the remnant lipoproteins that contain defective isoforms of human ApoE induce foam cell formation via a mechanism involving induction of ER stress. We will test this hypothesis with three specific aims.
Specific aim 1 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE regulate the expression of genes related to foam cell formation.
Specific aim 2 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE regulate gene expression by activation of ER stress-related signaling pathways.
Specific aim 3 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE induce foam cell formation by activation of ER stress-related signaling pathways. If our hypothesis is correct, inhibition of ER stress-related signaling pathways would attenuate ApoE-deficient remnant lipoprotein-induced changes in macrophage lipid catabolism and foam cell formation-related gene expression, and suppress foam cell formation.

Public Health Relevance

This proposal studies the involvement of unfolded protein response in foam cell formation, an early stage of atherosclerosis. Data derived from this project will contribute to understanding of the mechanism of atherosclerosis, and provide therapeutic strategies for myocardial infarction and stroke induced by atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1-MBRS-X (GC))
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Liu, Lijuan
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Meharry Medical College
Other Basic Sciences
Schools of Medicine
United States
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Okoro, Emmanuel U; Guo, Zhongmao; Yang, Hong (2016) Akt isoform-dependent regulation of ATP-Binding cassette A1 expression by apolipoprotein E. Biochem Biophys Res Commun 477:123-8
Miao, LiXia; Okoro, Emmanuel U; Cao, ZhiJan et al. (2015) High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells. Biochem Biophys Res Commun 465:256-61
Shan, Guang; Yang, Fang; Zhou, LiChun et al. (2015) Increase in Blood Glutathione and Erythrocyte Proteins Related to Glutathione Generation, Reduction and Utilization in African-American Old Women with Diabetes. J Sci Technol Environ 5:
Okoro, Emmanuel U; Zhang, Hongfeng; Guo, Zhongmao et al. (2015) A Subregion of Reelin Suppresses Lipoprotein-Induced Cholesterol Accumulation in Macrophages. PLoS One 10:e0136895
Wu, Jianhua; Xiao, Yanhong; Liu, Juang et al. (2014) Potential role of ATM in hepatocyte endocytosis of ApoE-deficient, ApoB48-containing lipoprotein in ApoE-deficient mice. Int J Mol Med 33:462-8
Zhou, LiChun; Yang, Hong; Okoro, Emmanuel U et al. (2014) Up-regulation of cholesterol absorption is a mechanism for cholecystokinin-induced hypercholesterolemia. J Biol Chem 289:12989-99
Zhou, Lichun; Yang, Dezhi; Wu, Dong Fang et al. (2013) Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice. ISRN Pharmacol 2013:847310
Lin, Xinghua; Yang, Hong; Zhang, Hongfeng et al. (2013) A novel transcription mechanism activated by ethanol: induction of Slc7a11 gene expression via inhibition of the DNA-binding activity of transcriptional repressor octamer-binding transcription factor 1 (OCT-1). J Biol Chem 288:14815-23
Okoro, Emmanuel Ugochukwu; Zhao, Yanfeng; Guo, ZhongMao et al. (2012) Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway. PLoS One 7:e44430
Chen, Xinping; Guo, Zhongmao; Okoro, Emmanuel U et al. (2012) Up-regulation of ATP binding cassette transporter A1 expression by very low density lipoprotein receptor and apolipoprotein E receptor 2. J Biol Chem 287:3751-9

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