Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake
Ferrari A, Whang E, Xiao X, Kennelly JP, Romartinez-Alonso B, Mack JJ, Weston T, Chen K, Kim Y, Tol MJ, Bideyan L, Nguyen A, Gao Y, Cui L, Bedard AH, Sandhu J, Lee SD, Fairall L, Williams KJ, Song W, Munguia P, Russell RA, Martin MG, Jung ME, Jiang H, Schwabe JWR, Young SG, Tontonoz P
Science (New York, N.Y.) · 56 citations
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- Animals
- Main outcome
- Health markers and function
Who paid for it
- Funding
- Independent funding
- Nonprofit
- American Diabetes Association
- Nonprofit
- American Heart Association
- Nonprofit
- Damon Runyon Cancer Research Foundation
- Government
- Australian Government
- University or hospital
- UCSD-UCLA Diabetes Research Center
- Nonprofit
- Fondation Leducq
- University or hospital
- Wuhan University
- Government
- National Institutes of Health
- University or hospital
- University of California, San Diego
- Government
- National Heart, Lung, and Blood Institute
- Government
- National Institute of Diabetes and Digestive and Kidney Diseases
- Government
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Government
- NICHD NIH HHS
- Government
- NIDDK NIH HHS
- Government
- NHLBI NIH HHS
- Grants
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK126779); American Heart Association (903306); National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK063491); National Heart, Lung, and Blood Institute (P01 HL146358); National Institutes of Health (NIH K12); National Heart, Lung, and Blood Institute (R35 HL139725); National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007180); University of California, San Diego (DK063491); Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12 HD111040); National Institute of Diabetes and Digestive and Kidney Diseases (RC2 DK118640); National Institutes of Health (T32DK007180); National Institutes of Health (DK126779); National Institutes of Health (DK-063491); National Institutes of Health (HL146358)
Based on 15 listed funder(s).
Publication
- Published
- 2023-11-09 · Science · vol. 382 · issue 6671 · p. eadf0966
- Publisher
- American Association for the Advancement of Science
- Cited
- 58 citations · more than 98% of similar papers · 6.6× the field average
- Impact
- Top 10% most cited in its field
- References
- 69 works
- Access
- Open access (repository copy)
- Research areas
- Drug Transport and Resistance Mechanisms · Cholesterol and Lipid Metabolism · Glycosylation and Glycoproteins Research
- Keywords
- Cholesterol, Advanced Spaceborne Thermal Emission and Reflection Radiometer, Endoplasmic reticulum, Brush border, Biology, Chemistry, Biochemistry, Internal medicine, Cell biology, Membrane, Medicine
- MeSH
- enterocytes, jejunum, animals, mice, inbred c57bl, mice, knockout, humans, mice, cholesterol, dietary, membrane transport proteins, membrane proteins, biological transport, intestinal absorption, liver x receptors
28 authors
From US, GB, AU, HK
- Alessandra Ferrari · correspondingUniversity of California, Los Angeles
- Emily C. Whang · correspondingUniversity of California, Los Angeles
- Xiao XuUniversity of California, Los Angeles
- John Paul KennellyUniversity of California, Los Angeles
- Beatriz Romartínez-AlonsoUniversity of Leicester
- Julia J. MackUniversity of California, Los Angeles
Abstract
Intestinal 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.
Abstract via Europe PMC. Copyright remains with the authors or publisher.
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