UBC Theses and Dissertations
Regulation of ATP-binding cassette transporter A1 In intimal-type arterial smooth muscle cells Pannu, Parveer Singh
The removal of cholesterol from cells and formation of high-density lipoprotein (HDL) particles is critically dependent on the membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1). Previous studies from the Francis laboratory have determined that the regulation of ATP-binding cassette transporter A1 (ABCA1) expression is impaired in model intimal-type arterial smooth muscle cells (SMCs) and human intimal SMCs in atherosclerotic coronary arteries, providing a novel explanation for cholesterol accumulation and foam cell formation in human atheroma. Growing evidence appears to emphasize the importance of the lysosomal-mitochondrial oxysterol pathway in regulating ABCA1 expression. We hypothesized that the reduced expression of ABCA1 in model intimal-type arterial SMCs is due to impaired enzyme sterol 27-hydroxylase (CYP27A1) expression, resulting in impaired oxysterol production critical for the activation of ABCA1 gene expression via the Liver X receptor (LXR) pathway. Our results show that intimal-type arterial SMCs exhibit a reduced expression of CYP27A1 mRNA and protein. Exogenous treatment of these cells with LXR agonists increases ABCA1 expression, indicating an intact LXR-mediated activation of ABCA1 gene expression. Despite successful transfection of CYP27A1 in these SMCs, intimal-type arterial SMCs do not increase their expression of ABCA1. The expression of steroidogenic acute regulatory protein D1 (StARD1), responsible for the delivery of cholesterol to CYP27A1, is also reduced in intima-type SMCs. We also show preliminary results of reduced human arterial intimal SMC-specific CYP27A1 expression in coronary arteries with native atherosclerosis. The findings of this thesis provide a narrative highlighting the importance of the intracellular transport of cholesterol via StaRD1 to CYP27A1 for the activation of LXR-dependent ABCA1 expression in arterial SMCs, and provide further insight into the dysregulation of ABCA1 expression in human atherosclerotic arterial SMCs that may contribute to the foam cell population and subsequent plaque formation in human atherogenesis.
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