Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 432, Issue 17, Pages 4922-4941Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2020.07.006
Keywords
ABC transporter; atherosclerosis; cholesterol homeostasis; macrophages; reverse cholesterol transport
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Funding
- CSIR-Indian Institute of Chemical Biology, Kolkata [MLP-115]
- DST-SERB [DST-SERB NPDF/2016/000540]
- CSIR, New Delhi
- Department of Science and Technology, Government of India (SERB) [EMR/2016/001333]
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Cholesterol homeostasis results from a delicate interplay between influx and efflux of free cholesterol primarily mediated by ABCA1. Here we report downregulation of ABCA1 in hyper-cholesterol conditions in macrophages, which might be responsible for compromised reverse cholesterol transport and hyperlipidemia. Surprisingly, this is countered by the upregulation of a lesser known family member ABCA5 to maintain cholesterol efflux. The relative contribution of ABCA1 and ABCA5 toward cholesterol efflux was evaluated and revealed ABCA5 as the primary efflux mediator under high cholesterol load. These observations were correlated to cholesterol load in circulation in vivo, and we observed an inverse expression profile in mice models of atherosclerosis (ApoE(-/)(-)) and hyperlipidemia (PPAR alpha(-/)(-)) in response to high cholesterol diet. Observations were further validated in human plasma samples. Simulation studies revealed a unique conformation of ABCA5 proposing a favored route for cholesterol loading onto high-density lipoproteins for reverse cholesterol transport. Thus, our study implicates a functional complementation between these two transporters, formulating an efficient strategy to maintain efflux in cholesterol excess conditions in macrophages. (C) 2020 Elsevier Ltd. All rights reserved.
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