Intracellular cholesterol transport

Intracellular cholesterol transport refers to the multifaceted processes that move cholesterol between subcellular compartments such as the endoplasmic reticulum (ER), endosomes, Golgi, plasma membrane, and mitochondria to maintain cellular cholesterol homeostasis. This transport occurs via vesicular trafficking, nonvesicular mechanisms involving lipid transfer proteins (e.g., ORPs, StAR-related proteins like StAR and MLN64/STARD3), and membrane contact sites, countering cholesterol's hydrophobicity that limits spontaneous diffusion. Key pathways include rapid export of newly synthesized cholesterol from the cholesterol-poor ER to the plasma membrane, endosomal efflux regulated by NPC1/NPC2 for esterification or recycling, and delivery to mitochondria for steroidogenesis via StAR. Dysregulation disrupts sterol sensing by SCAP-Insig-SREBP pathways, leading to altered cholesterol synthesis, uptake, and efflux via transporters like ABCA1 and ABCG5/G8. In disease, defects cause lysosomal cholesterol accumulation in Niemann-Pick type C or impaired biosynthesis in Smith-Lemli-Opitz syndrome, contributing to neurodegeneration, atherosclerosis, and metabolic disorders, though no drugs directly target the process as a whole—instead modulating related proteins like HMGCR or NPC1. Overall, it underpins membrane composition, signaling, and lipid metabolism without a single molecular entity amenable to conventional therapeutic targeting.