Niemann-Pick C1-Like 1 intracellular cholesterol transporter (NPC1L1)

NPC1L1 is a multipass membrane protein primarily expressed in intestinal epithelial cells and hepatocytes that plays a central role in cholesterol absorption. The protein contains a sterol-sensing domain (SSD) and an N-terminal domain (NTD) that are critical for its function. NPC1L1 mediates the uptake of dietary cholesterol across the plasma membrane of intestinal enterocytes through a complex mechanism involving cholesterol binding and protein conformational changes. Structural studies have revealed that NPC1L1 exists in different conformational states. In the apo (unbound) form, it adopts an "open state" where the N-terminal domain interacts loosely with the rest of the protein, allowing cholesterol loading. When cholesterol levels increase, the SSD binds more cholesterol molecules, triggering the formation of a stable structural cluster that facilitates cholesterol transport. In contrast, when ezetimibe binds to NPC1L1, it causes deformation of the SSD and destroys this structural cluster, thereby inhibiting NPC1L1 function. The cholesterol transport mechanism involves dynamic movement between cellular compartments. Under cholesterol-depleted conditions, NPC1L1 moves from the endocytic recycling compartment to the plasma membrane; when cholesterol is replenished, NPC1L1 is internalized. This trafficking is essential for NPC1L1-mediated cholesterol uptake and is disrupted by ezetimibe binding. People with inactivating mutations in the NPC1L1 gene have lower LDL cholesterol levels and approximately 50% reduced risk of coronary heart disease, validating this protein as an important therapeutic target for cardiovascular disease prevention.

Other names

NPC1-like intracellular cholesterol transporter 1NPC11L1SLC65A2LDLCQ7

Ezetimibe binds to NPC1L1, causing deformation of the sterol-sensing domain (SSD); Disrupts the structural cluster in the SSD necessary for cholesterol transport; Inhibits cholesterol-regulated trafficking of NPC1L1 between plasma membrane and endocytic recycling compartment; Blocks cholesterol absorption in intestinal enterocytes