Cholesterol, the central lipid of mammalian cells

Abstract

Despite its importance for mammalian cell biology and human health, there are many basic aspects of cholesterol homeostasis that are not well understood. Even for the well-characterized delivery of cholesterol to cells via lipoproteins, a novel regulatory mechanism has been discovered recently, involving a serum protein called PCSK9, which profoundly affects lipoproteins and their receptors. Cells can export cholesterol by processes that require the activity of ABC transporters, but the molecular mechanisms for cholesterol transport remain unclear. Cholesterol levels in different organelles vary by 5-10-fold, and the mechanisms for maintaining these differences are now partially understood. Several proteins have been proposed to play a role in the inter-organelle movement of cholesterol, but many aspects of the mechanisms for regulating intracellular transport and distribution of cholesterol remain to be worked out. The endoplasmic reticulum is the main organelle responsible for regulation of cholesterol synthesis, and careful measurements have shown that the proteins responsible for sterol sensing respond over a very narrow range of cholesterol concentrations to provide very precise, switch-like control over cholesterol synthesis.

Figure 1. Cholesterol homeostasis in mammalian cells

(A) Insertion of cholesterol from detergent micelles in the intestinal lumen into the apical membrane of enterocytes requires NPC1L1. The N-terminal extracellular loop of NPC1L1 may lift cholesterol across the glycocalyx as has been proposed for NPC1: (B) Soluble NPC2 extracts cholesterol from endocytosed LDL and hands it over to the cholesterol-binding lumenal loop 1 of NPC1. NPC1 may chaperone the hydrophobic cholesterol across the glycocalyx into the limiting membrane, which is followed by spontaneous transmembrane translocation and egress. (C) When the cholesterol concentration of the ER gets below 5 mol%, this results in release of the SCAP-SREBP complex from Insig into COPII vesicles and transport to the Golgi, where the subsequent action of the two endoproteases S1P and S2P releases the SREBP transcription factor that binds to sterol-responsive elements in the DNA and regulates transcription. (D) Extrusion of cholesterol by the ABC transporter ABCA1 from the cytoplasmic leaflet, across the plasma membrane onto lipid-poor apolipoprotein A1 releases cholesterol from peripheral tissues.