{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNiemann‐Pick C1‐Like 1 (NPC1L1) is a multitransmembrane protein that plays a central role in whole‐body cholesterol homeostasis. It is prominently expressed on the apical brush border of intestinal enterocytes and in hepatocytes where it mediates the uptake of dietary and biliary cholesterol, thereby contributing critically to plasma low‐density lipoprotein levels and overall lipoprotein metabolism. Its discovery as the molecular target of ezetimibe has provided a mechanistic basis for a new cholesterol‐lowering strategy, since blocking NPC1L1 function substantially reduces intestinal cholesterol absorption."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, NPC1L1 binds cholesterol via its amino‐terminal domain and facilitates its internalization through a clathrin/AP2‐dependent endocytic pathway. Numerous studies have demonstrated that inhibition of NPC1L1 internalization—either through genetic mutations that impair its recycling or via pharmacological blockade by ezetimibe—results in reduced cholesterol uptake. The protein’s regulated trafficking involves association with microfilaments and other key proteins (for example, flotillins), and its proper glycosylation, recycling, and dimerization are essential for efficient cholesterol transport. Moreover, mutations within critical extracellular loops or in sterol‐sensing regions significantly modulate its function and are linked to variable responsiveness to ezetimibe and alterations in plasma LDL‐cholesterol levels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in cholesterol uptake, NPC1L1 has been implicated in the intestinal absorption of other lipophilic molecules such as fat‐soluble vitamins – notably vitamin E and vitamin K – and even certain carotenoids, although it does not appear to mediate all such substrates equally. Moreover, by influencing cholesterol re‐absorption in the liver, NPC1L1 contributes to biliary cholesterol homeostasis and has been associated with conditions ranging from coronary heart disease to gallstone formation. Notably, its function has extended into studies of viral infections, where NPC1L1 has been shown to facilitate the cell-to-cell spread of hepatitis C virus, highlighting its broader impact on human pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variation in NPC1L1, including both common and rare non‐synonymous alleles, has been shown to influence cholesterol absorption efficiency, modulate plasma LDL‐cholesterol levels, and affect therapeutic responses to lipid‐lowering regimens. Recent structural studies, including cryo-electron microscopy analyses, have revealed that NPC1L1 functions as a homodimer with specific transmembrane and sterol-sensing domains necessary for substrate transfer. In addition, the transcriptional regulation of NPC1L1 by factors such as SREBP2, HNF4α, and PPARα has been elucidated, providing insight into its dynamic response to metabolic cues and dietary cholesterol. These findings collectively underscore the physiological and clinical relevance of NPC1L1 as a target for both pharmacological intervention and precision medicine strategies addressing dyslipidemia and related disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Scott W Altmann, Harry R Davis, Li-Ji Zhu, et al. 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