Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Alessandra Ferrari; Emily Whang; Xu Xiao; John P Kennelly; Beatriz Romartinez-Alonso; Julia J Mack; Thomas Weston; Kai Chen; Youngjae Kim; Marcus J Tol; Lara Bideyan; Alexander Nguyen; Yajing Gao; Liujuan Cui; Alexander H Bedard; Jaspreet Sandhu; Stephen D Lee; Louise Fairall; Kevin J Williams; Wenxin Song; Priscilla Munguia; Robert A Russell; Martin G Martin; Michael E Jung; Haibo Jiang; John W R Schwabe; Stephen G Young; Peter Tontonoz

doi:10.1126/science.adf0966

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Alessandra Ferrari, Emily Whang, Xu Xiao, John P Kennelly, Beatriz Romartinez-Alonso, Julia J Mack, Thomas Weston, Kai Chen, Youngjae Kim, Marcus J Tol, Lara Bideyan, Alexander Nguyen, Yajing Gao, Liujuan Cui, Alexander H Bedard, Jaspreet Sandhu, Stephen D Lee, Louise Fairall, Kevin J Williams, Wenxin SongPriscilla Munguia, Robert A Russell, Martin G Martin, Michael E Jung, Haibo Jiang, John W R Schwabe, Stephen G Young, Peter Tontonoz

School of Molecular Sciences

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Article number	eadf0966
Pages (from-to)	eadf0966
Journal	Science (New York, N.Y.)
Volume	382
Issue number	6671
DOIs	https://doi.org/10.1126/science.adf0966
Publication status	Published - 1 Nov 2023

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Ferrari, 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., ... Tontonoz, P. (2023). Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake. Science (New York, N.Y.), 382(6671), eadf0966. Article eadf0966. https://doi.org/10.1126/science.adf0966

@article{250b68d64b084da4848cd4df9e2690b8,

title = "Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake",

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.",

author = "Alessandra Ferrari and Emily Whang and Xu Xiao and Kennelly, {John P} and Beatriz Romartinez-Alonso and Mack, {Julia J} and Thomas Weston and Kai Chen and Youngjae Kim and Tol, {Marcus J} and Lara Bideyan and Alexander Nguyen and Yajing Gao and Liujuan Cui and Bedard, {Alexander H} and Jaspreet Sandhu and Lee, {Stephen D} and Louise Fairall and Williams, {Kevin J} and Wenxin Song and Priscilla Munguia and Russell, {Robert A} and Martin, {Martin G} and Jung, {Michael E} and Haibo Jiang and Schwabe, {John W R} and Young, {Stephen G} and Peter Tontonoz",

year = "2023",

month = nov,

day = "1",

doi = "10.1126/science.adf0966",

language = "English",

volume = "382",

pages = "eadf0966",

journal = "Science (New York, N.Y.)",

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number = "6671",

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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 2023, 'Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake', Science (New York, N.Y.), vol. 382, no. 6671, eadf0966, pp. eadf0966. https://doi.org/10.1126/science.adf0966

TY - JOUR

T1 - Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

AU - Ferrari, Alessandra

AU - Whang, Emily

AU - Xiao, Xu

AU - Kennelly, John P

AU - Romartinez-Alonso, Beatriz

AU - Mack, Julia J

AU - Weston, Thomas

AU - Chen, Kai

AU - Kim, Youngjae

AU - Tol, Marcus J

AU - Bideyan, Lara

AU - Nguyen, Alexander

AU - Gao, Yajing

AU - Cui, Liujuan

AU - Bedard, Alexander H

AU - Sandhu, Jaspreet

AU - Lee, Stephen D

AU - Fairall, Louise

AU - Williams, Kevin J

AU - Song, Wenxin

AU - Munguia, Priscilla

AU - Russell, Robert A

AU - Martin, Martin G

AU - Jung, Michael E

AU - Jiang, Haibo

AU - Schwabe, John W R

AU - Young, Stephen G

AU - Tontonoz, Peter

PY - 2023/11/1

Y1 - 2023/11/1

N2 - 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.

AB - 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.

U2 - 10.1126/science.adf0966

DO - 10.1126/science.adf0966

M3 - Article

C2 - 37943936

SN - 0036-8075

VL - 382

SP - eadf0966

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6671

M1 - eadf0966

ER -

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Abstract

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