Cellular itinerary of LDL cholesterol

Abstract

Cholesterol is an essential component of eukaryotic cells. This lipid is synthesized on endoplasmic reticulum (ER) membranes and can also be supplied to cells extracellularly via lipoprotein particles such as low-density lipoproteins (LDLs). These cholesterol-carrying LDL particles bind to transmembrane LDL receptors in the plasma membrane (PM) and are internalized into cells via receptor-mediated endocytosis (1). Mutations in the LDL receptor gene cause the human disease familial hypercholesterolemia in which LDL cholesterol accumulates in plasma, thereby promoting atherosclerosis and heart disease (2). The endocytosed LDL particles are delivered to lysosomes where the LDL cholesterol is released and exported to the PM. Subsequently, the cholesterol is transferred from the PM to the ER, the site at which cellular cholesterol content is tightly regulated by genes encoding several membrane-associated proteins (1). When the cholesterol content of the ER exceeds ∼5% of the total lipid mass of the ER, the synthesis of cholesterol and the production of LDL receptors in the ER are down-regulated (3). In addition, excess cholesterol in the ER is esterified to cholesteryl esters for storage in lipid droplets. This stringent regulation of cholesterol homeostasis is essential for normal cell viability and growth. Previous studies by Trinh et al. (4), and from the laboratories of Tontonoz (5) and Saheki (6), have shown that the transport of cholesterol from the PM to the ER in mammalian cells requires the anionic phospholipid phosphatidylserine (PS), as well as the ER- and PM-associated Aster proteins (Fig. 1). However, it was not clear whether PS and the Aster proteins operated together or independently in this pathway. In PNAS, Trinh et al. (7) establish that, although PS and the Aster proteins largely act together in PM-to-ER cholesterol transport, the two factors also partially function independently of one another in this pathway. Fig. 1. Movement of cholesterol from the PM to … [↵][1] 1Email: jean.vance{at}ualberta.ca. [1]: #xref-corresp-1-1

Topics & Concepts