Cellular cholesterol trafficking pathways

Cellular cholesterol trafficking pathways encompass the complex network of vesicular and non-vesicular transport mechanisms that maintain cholesterol homeostasis within and between cellular compartments (Ikonen, 2023). These pathways involve the uptake of extracellular cholesterol via the LDL receptor, its transport through the endo-lysosomal system—critically mediated by the Niemann-Pick C1 (NPC1) and NPC2 proteins—and its subsequent distribution to the plasma membrane and endoplasmic reticulum (ER) (Lyu et al., 2019; Physiology.org). Cholesterol is also synthesized in the ER and moved to other membranes via sterol transfer proteins such as oxysterol-binding proteins (OSBPs) and Aster proteins (Cell, 2018; NIH). Dysregulation of these pathways is central to the pathogenesis of atherosclerosis, where impaired efflux leads to foam cell formation, and Niemann-Pick Type C disease, a fatal lysosomal storage disorder (Physiology.org; NIH). Furthermore, cholesterol trafficking is an emerging target in oncology and angiogenesis, as it modulates key signaling pathways including mTOR and VEGFR2 (Lyu et al., 2019; PNAS, 2010). Pharmacological agents such as itraconazole and astemizole disrupt these pathways by binding to the sterol-sensing domain of NPC1, while cyclodextrins are utilized to mobilize sequestered cholesterol in therapeutic contexts (Lyu et al., 2019; Purdue.edu).

Other names

Intracellular cholesterol transportCholesterol handlingCholesterol fluxSterol traffickingVesicular and non-vesicular cholesterol transport

Inhibition of lysosomal cholesterol egress via NPC1 binding, modulation of non-vesicular transport through sterol transfer proteins, and activation of nuclear receptors (LXR/RXR) to promote cholesterol efflux and reduce intracellular accumulation.