ArticleProceedings of the National Academy of Sciences of the United States of America2008
Extracellular loop C of NPC1L1 is important for binding to ezetimibe.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 114 citations in OpenAlex.
- Ergosterol as a natural modulator of intestinal cholesterol absorption via NPC1L1: anFrontiers in bioinformatics · 2026Article
- The Role of Cholesterol Metabolism and Its Regulation in Tumor Development.Cancer medicine · 2025Review
- In silico comparative analysis of cestode and human NPC1 provides insights for ezetimibe repurposing to visceral cestodiases treatment.Scientific reports · 2024Article
- Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers.Journal of experimental & clinical cancer research : CR · 2024Review
- Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake.Science (New York, N.Y.) · 2023Article
- Fluorescent visualization and evaluation of NPC1L1-mediated vesicular endocytosis during intestinal cholesterol absorption in mice.Life metabolism · 2023Article
- The role of cholesterol metabolism in tumor therapy, from bench to bed.Frontiers in pharmacology · 2023Review
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- Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake.Science advances · 2021Article
- Synthesis and Modeling of Ezetimibe Analogues.Molecules (Basel, Switzerland) · 2021Article
- Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition.Science advances · 2020Article
- Article
- Mechanisms and regulation of cholesterol homeostasis.Nature reviews. Molecular cell biology · 2020Review
- The Effect of Polyphenols on Hypercholesterolemia through Inhibiting the Transport and Expression of Niemann-Pick C1-Like 1.International journal of molecular sciences · 2019Review
- NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains.Journal of lipid research · 2018Article
- Lipid Lowering Therapy and Circulating PCSK9 Concentration.Journal of atherosclerosis and thrombosis · 2017Review
- Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K.Journal of atherosclerosis and thrombosis · 2017Review
- Impact of a high-cholesterol diet on expression levels of Niemann-Pick C1-like 1 and intestinal transporters in rats and mice.European journal of drug metabolism and pharmacokinetics · 2016Article
- Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis.Molecular biology of the cell · 2016Article
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Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Niemann-Pick C1-like protein (NPC1L1) mediates the absorption of dietary cholesterol in the proximal region of the intestine, a process that is blocked by cholesterol absorption inhibitors (CAIs), including ezetimibe (EZE). Using a proteomic approach, we demonstrate that NPC1L1 is the protein to which EZE and its analogs bind. Next, we determined the site of interaction of EZE analogs with NPC1L1 by exploiting the different binding affinities of mouse and dog NPC1L1 for the radioligand analog of EZE, [(3)H]AS. Chimeric and mutational studies indicate that high-affinity binding of [(3)H]AS to dog NPC1L1 depends on molecular determinants present in a 61-aa region of a large extracellular domain (loop C), where Phe-532 and Met-543 appear to be key contributors. These data suggest that the [(3)H]AS-binding site resides in the intestinal lumen and are consistent with preclinical data demonstrating in vivo efficacy of a minimally bioavailable CAI. Furthermore, these determinants of [(3)H]AS binding lie immediately adjacent to a hotspot of human NPC1L1 polymorphisms correlated with hypoabsorption of cholesterol. These observations, taken together with the recently described binding of cholesterol to the N terminus (loop A) of the close NPC1L1 homologue, NPC1, may provide a molecular basis for understanding EZE inhibition of NPC1L1-mediated cholesterol absorption. Specifically, EZE binding to an extracellular site distinct from where cholesterol binds prevents conformational changes in NPC1L1 that are necessary for the translocation of cholesterol across the membrane.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.