Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

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dc.contributor.authorFerrari, Aen_AU
dc.contributor.authorWhang, Een_AU
dc.contributor.authorXiao, Xen_AU
dc.contributor.authorKennelly, JPen_AU
dc.contributor.authorRomartinez-Alonso, Ben_AU
dc.contributor.authorMack, JJen_AU
dc.contributor.authorWeston, Ten_AU
dc.contributor.authorChen, Ken_AU
dc.contributor.authorKim, Yen_AU
dc.contributor.authorTol, MJen_AU
dc.contributor.authorBideyan, Len_AU
dc.contributor.authorNguyen, Aen_AU
dc.contributor.authorGao, YJen_AU
dc.contributor.authorCui, LJen_AU
dc.contributor.authorBedard, AHen_AU
dc.contributor.authorSandhu, Jen_AU
dc.contributor.authorLee, SDen_AU
dc.contributor.authorFairall, Len_AU
dc.contributor.authorWilliams, KJen_AU
dc.contributor.authorSong, WXen_AU
dc.contributor.authorMunguia, Pen_AU
dc.contributor.authorRussell, RAen_AU
dc.contributor.authorMartin, MGen_AU
dc.contributor.authorJung, MEen_AU
dc.contributor.authorJiang, Hen_AU
dc.contributor.authorSchwabe, JWRen_AU
dc.contributor.authorYoung, SGen_AU
dc.contributor.authorTontonoz, Pen_AU
dc.date.accessioned2024-02-22T23:59:42Zen_AU
dc.date.available2024-02-22T23:59:42Zen_AU
dc.date.issued2023-11-10en_AU
dc.date.statistics2024-02-23en_AU
dc.description.abstractIntestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. © 2023 The Authors, exclusive licensee American Association for the Advancement of Science.en_AU
dc.description.sponsorshipWe thank L. Fong, P. Kim, and E. Tokhtaeva for the technical assistance. We also thank members of the Tontonoz, Tarling-Vallim, Edwards, Villanueva, Young, and Bensinger labs at UCLA for useful advice and discussions and for sharing reagents and resources. We thank G. Su and the UCLA Lipidomics and Y. Li and the UCLA Translational Pathology Core Laboratory. pALOD4 was a gift from Arun Radhakrishnan (Addgene plasmids # 111026). We thank B.-L. Song at Wuhan University for the NPC1L1-EGFP construct and NPC1L1 KO mice. We thank T. Darwish for supporting the production of [2H]cholesterol.en_AU
dc.format.mediumPrint-Electronicen_AU
dc.identifier.citationFerrari, A., Whang, E., Xiao, X., Kennelly, J. P., Romartinez-Alonso, B., Mack, J. J., Weston, T., Chen, K., Kim, Y., Tol, M. J., Bideyan, L. Nguyen, A. Gao, Y., Cui, L., Bedard, A. H., Sandhu, J., Lee, S. D., Fairall, L., Williams, K. J., Song, W., Munguia, P., Russell, R. A., Martin, M. G., Jung, M. E., Jiang, H., Schwabe, J. W. R., Young, S. G., & Tontonoz, P. (2023). Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake. Science, 382(6671). doi:10.1126/science.adf0966en_AU
dc.identifier.issn0036-8075en_AU
dc.identifier.issn1095-9203en_AU
dc.identifier.issue6671en_AU
dc.identifier.journaltitleScienceen_AU
dc.identifier.urihttp://dx.doi.org/10.1126/science.adf0966en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15400en_AU
dc.identifier.volume382en_AU
dc.languageEnglishen_AU
dc.language.isoenen_AU
dc.publisherAmerican Association for the Advancement of Science (AAAS)en_AU
dc.subjectCholesterolen_AU
dc.subjectDieten_AU
dc.subjectRadionuclide kineticsen_AU
dc.subjectIntestinal Absorptionen_AU
dc.subjectHomeostasisen_AU
dc.subjectMembranesen_AU
dc.subjectLipidsen_AU
dc.titleAster-dependent nonvesicular transport facilitates dietary cholesterol uptakeen_AU
dc.typeJournal Articleen_AU
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