Mechanism of dietary cholesterol uptake by niemann-pick C1-like 1 protein
- Cholesterol is an essential biomolecule playing a number of key physiological roles; disruption of its homeostasis can result in developmental errors, illness or premature death. NPC1L1 plays an important role in cholesterol regulation by mediating its dietary uptake and biliary re-uptake. However, the mechanism of its action and how the drug, Ezetimibe, inhibits NPC1L1 are poorly understood. In this project, we have shown that the existing model that suggested NPC1L1-mediated cholesterol uptake requires endocytosis, and that Ezetimibe works by blocking endocytosis is incorrect. Endocytosis is not involved in NPC1L1-mediated cholesterol uptake or function. We have proposed an alternative, though still incomplete mechanism, based on the similarity between the lysosomal protein NPC1 and NPC1L1. Our data suggest that the N-terminal domain and domain 2 of NPC1L1 require an interaction for both cholesterol uptake and Ezetimibe binding. In addition, we have demonstrated that a functional sterol sensing domain is required for NPC1L1 protein function. Finally, we have shown that microsomal triglyceride transfer protein is involved in regulating the biosynthesis of NPC1L1.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Johnson, Tory A
|Stanford University, Department of Biochemistry.
|Statement of responsibility
|Tory A. Johnson.
|Submitted to the Department of Biochemistry.
|Thesis (Ph.D.)--Stanford University, 2017.
- © 2017 by Victoria Anne Johnson
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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