Regulation of ABCA1 Expression During Apoptotic Cell Engulfment
Fond, Aaron, Microbiology - Graduate School of Arts and Sciences, University of Virginia
Ravichandran, Kodi, Microbiology, Immunology, and Cancer Biology, University of Virginia
The transporter ABCA1 plays a key role in cholesterol efflux from macrophages, which is linked to protection against cardiovascular disease. During apoptotic cell clearance, macrophages uptake boluses of cholesterol from their targets, but how they maintain homeostasis during this process is poorly understood. In this dissertation, we describe a newly identified pathway in ABCA1 regulation initiated by the engulfment receptor BAI1 and its downstream signaling intermediates ELMO1 and Rac1. We found that the upregulation of ABCA1 in response to apoptotic cells does not require intake of cholesterol, and it is independent of the LXR sterol-sensing machinery. Both ‘loss of function’ studies using mice deficient in BAI1, ELMO1, and Rac1 and ‘gain of function’ studies in mice overexpressing BAI1 revealed the importance of this pathway. Furthermore, BAI1 deficiency in LDLR knockout mice display a serum lipid profile similar to that of mice with macrophage-specific deletion of ABCA1, whereas LDLR knockout mice overexpressing BAI1 display an increased in the proportion of HDL in their serum, which is the product of ABCA1 activity. Although deletion of BAI1 did not exacerbate atherosclerosis as measured by aortic root plaque formation, there was a measurable increase in macrophages and apoptotic cells in the plaques, supporting the role of BAI1 as an apoptotic cell engulfment receptor. Furthermore, in the LDLR deficient mice, we found that BAI1 deficiency resulted in increased weight gain and adiposity whereas BAI1 overexpression lessened weight gain on Western Diet. Collectively, these data reveal that the billions of cells that undergo apoptosis daily signal to regulate lipid homeostasis, and can do so through the BAI1-ELMO1-Rac1 pathway.
PHD (Doctor of Philosophy)
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