Novel Mechanism of Cholesterol Transport by ABCA5 in Macrophages and Its Role in Dyslipidemia.

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 (PPARα-/-) 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. Copyright © 2020 Elsevier Ltd. All rights reserved.

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Aleepta Guha Ray, Kamalika Roy Choudhury, Sandipan Chakraborty, Devasmita Chakravarty, Vivek Chander, Biman Jana, Khawer N Siddiqui, Arun Bandyopadhyay. Novel Mechanism of Cholesterol Transport by ABCA5 in Macrophages and Its Role in Dyslipidemia. Journal of molecular biology. 2020 Aug 07;432(17):4922-4941

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PMID: 32687853

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