NPC1, intracellular cholesterol trafficking and atherosclerosis

Abstract

Post-lysosomal cholesterol trafficking is an important, but poorly understood process that is essential to maintain lipid homeostasis. Niemann-Pick type C1 (NPC1), an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY), is known to accept cholesterol from NPC2 and then mediate cholesterol transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane in a vesicle- or oxysterol-binding protein (OSBP)-related protein 5 (ORP5)-dependent manner. Mutations in the NPC1 gene can be found in the majority of NPC patients, who accumulate massive amounts of cholesterol and other lipids in the LE/LY due to a defect in intracellular lipid trafficking. Liver X receptor (LXR) is the major positive regulator of NPC1 expression. Atherosclerosis is the pathological basis of coronary heart disease, one of the major causes of death worldwide. NPC1 has been shown to play a critical role in the atherosclerotic progression. In this review, we have summarized the role of NPC1 in regulating intracellular cholesterol trafficking and atherosclerosis.

Keywords: ABCA1; ATP-binding cassette transporter A1; Atherosclerosis; COX-2; Cholesterol; DHC; ER; ERK1/2; LDL; LDL-C; LDL-cholesterol; LDLR; LE/LY; LXR; N-terminal domain; NPC1; NPC2; NTD; Niemann-Pick type C1; ORP5; OSBP; OSBP­related protein 5; PPARα; SREBP; SSD; TGN; apoA-I; apoE; apolipoprotein A-I; apolipoprotein E; cyclooxygenase-2; dihydrocapsaicin; endoplasmic reticulum; extracellular signal-regulated kinase 1/2; late endosome/lysosome; liver X receptor; low-density lipoprotein; low-density lipoprotein receptor; oxLDL; oxidized low-density lipoprotein; oxysterol­binding protein; peroxisome proliferator-activated receptor α; sterol regulatory element-binding protein; sterol-sensing domain; trans-Golgi network.