Abstract
Cholesterol is an essential molecule in cellular membranes, but too much cholesterol can be toxic. Therefore, mammalian cells have developed complex mechanisms to remove excess cholesterol. In this review article, we discuss what is known about such efflux pathways including a discussion of reverse cholesterol transport and formation of high-density lipoprotein, the function of ABC transporters and other sterol efflux proteins, and we highlight their role in human diseases. Attention is paid to the biophysical principles governing efflux of sterols from cells. We also discuss recent evidence for cholesterol efflux by the release of exosomes, microvesicles, and migrasomes. The role of the endo-lysosomal network, lipophagy, and selected lysosomal transporters, such as Niemann Pick type C proteins in cholesterol export from cells is elucidated. Since oxysterols are important regulators of cellular cholesterol efflux, their formation, trafficking, and secretion are described briefly. In addition to discussing results obtained with traditional biochemical methods, focus is on studies that use established and novel bioimaging approaches to obtain insight into cholesterol efflux pathways, including fluorescence and electron microscopy, atomic force microscopy, X-ray tomography as well as mass spectrometry imaging.
Highlights
Upon activation liver X receptors (LXRs) together with isomers of retinoid X receptors (RXRs) will bind as heterodimers to their DNA response element (Figure 1) (Zhao and Dahlman-Wright, 2010). This will induce the transcription of genes that are involved in protecting the cell from becoming overloaded with cholesterol, including the ATPbinding cassette transporter A1 (ABCA1) which mediates the egress of phospholipids and cholesterol to acceptor proteins, such as apolipoprotein A-1 (Venkateswaran et al, 2000)
3) ABCA1 acts as a pump for lipids, like the aminophospholipid PS, or other hydrophobic substances at the cell surface, which is supported by its intrinsic ATPase activity and substrate specificity (Wang et al, 2001; Tall et al, 2002; Alder-Baerens et al, 2005; LinselNitschke and Tall, 2005; Quazi and Molday, 2013), 4) ABCA1 acts as cholesterol floppase, i.e. actively moving cholesterol from the inner to the outer plasma membrane (PM) leaflet for pick up by apolipoprotein A-1 (apoA1) (Ogasawara et al, 2019; Okamoto et al, 2020)
By growing the macrophages in the presence of fetal bovine serum and by activating cholesterol efflux via stimulation of LXRs and RXR complexes with agonists, He et al found that the particles became enriched with cholesterol accessible to ALO-D4, and that this cholesterol pool could be transferred to high-density lipoprotein (HDL) (He et al, 2018)
Summary
Cholesterol is a small lipid molecule consisting of a steroid ring system, a short alkyl-chain and a hydroxy group at position 3 as the only polar constituent These properties, together with the asymmetric orientation of its methyl groups, give cholesterol a unique ability to interact with phospholipids in cellular membranes. Cholesterol can be covalently attached to signaling proteins of the Hedgehog pathway, i.e., as a membrane anchor for Hedgehog and as a sensor to locate Smoothened to primary cilia (Garcia et al, 2001; Xiao et al, 2017) These diverse functions of cholesterol necessitate a tight control of its abundance in cellular membranes. We will start this review by introducing, how cholesterol synthesis and uptake are regulated before discussing mechanisms of cellular efflux of excess cholesterol
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