Routes and mechanisms of post‐endosomal cholesterol trafficking: A story that never ends

Abstract

Mammalian cells acquire most exogenous cholesterol through receptor-mediated endocytosis of low-density lipoproteins (LDLs). After internalization, LDL cholesteryl esters are hydrolyzed to release free cholesterol, which then translocates to late endosomes (LEs)/lysosomes (LYs) and incorporates into the membranes by co-ordinated actions of Niemann-Pick type C (NPC) 1 and NPC2 proteins. However, how cholesterol exits LEs/LYs and moves to other organelles remain largely unclear. Growing evidence has suggested that nonvesicular transport is critically involved in the post-endosomal cholesterol trafficking. Numerous sterol-transfer proteins (STPs) have been identified to mediate directional cholesterol transfer at membrane contact sites (MCSs) formed between 2 closely apposed organelles. In addition, a recent study reveals that lysosome-peroxisome membrane contact (LPMC) established by a non-STP synaptotagmin VII and a specific phospholipid phosphatidylinositol 4,5-bisphosphate also serves as a novel and important path for LDL-cholesterol trafficking. These findings highlight an essential role of MCSs in intracellular cholesterol transport, and further work is needed to unveil how various routes are regulated and integrated to maintain proper cholesterol distribution and homeostasis in eukaryotic cells.

GATA2 Expression by Intima-Infiltrating Macrophages Drives Early Atheroma Formation

“…The upregulation of GATA2 in intima-infiltrating macrophages and the dysregulation of multiple cholesterol-processing genes in the same cells suggest that GATA2 overexpression may drive defects in macrophage cholesterol homeostasis. RT-PCR analysis of intimainfiltrating macrophages confirmed that NPC1 and NPC2, which mediate the transfer of endocytosed cholesterol to cytosolic carrier proteins 43 , and ABCA1, which mediates the export of cholesterol from cells 6 , were downregulated in intima-infiltrating macrophages ( Figure 3A-C). This alteration in cholesterol uptake and efflux has previously been associated with abnormal cholesterol processing and foam cell development 44,45 .…”

Analysis of cholesterol export from endo-lysosomes by Niemann Pick C2 protein using combined fluorescence and X-ray microscopy

“…Cellular cholesterol homeostasis depends critically on sterol flux through LE/LYSs, but the pathways and molecular mechanisms of sterol trafficking between these organelles and other membranes are poorly defined 51,52 . In Niemann-Pick type C2 disease, cholesterol and other lipids build up due to lack of a small sterol-transfer protein, NPC2, in the lumen of LE/LYSs.…”

Lipid Transfer Proteins: Introduction to the Thematic Review Series

“…One set, the ORP discussed above in relation to PS enrichment, may transfer cholesterol to the plasma membrane. There are 12 family members in mammalian cells (27). The second set of cholesterol transfer proteins are StARD proteins containing START domain (Steroidogenic acute regulatory protein related lipid transfer) domain(s).…”