T cell cholesterol transport links intestinal immune responses to dietary lipid absorption

Yajing Gao^#^{1

2}, John P Kennelly^#^{1

2}, Xu Xiao^{1

2}, Emily Whang^{1

2

3}, Alessandra Ferrari^{1

2}, Alexander H Bedard^{1

2}, Julia J Mack^{4

5}, Alexander Nguyen^{1

2

6}, Sonal Srikanth⁷, Thomas Weston⁸, Lauren F Uchiyama^{1

2

5}, Whitaker Cohn⁹, Danielle H Cho^{1

2}, Min Sub Lee^{10

11}, Julian Whitelegge⁹, Yousang Gwack⁶, Stephen G Young^{4

7}, Steven J Bensinger^{10

11}, Peter Tontonoz^{1

2

5}

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ The Pasarow Mass Spectrometry Laboratory, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

^# Contributed equally.

PMID: 41066556
DOI: 10.1126/science.adt4169

T cell cholesterol transport links intestinal immune responses to dietary lipid absorption

Yajing Gao et al. Science. 2025.

. 2025 Oct 9;390(6769):eadt4169.

doi: 10.1126/science.adt4169. Epub 2025 Oct 9.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ The Pasarow Mass Spectrometry Laboratory, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

^# Contributed equally.

PMID: 41066556
DOI: 10.1126/science.adt4169

Abstract

The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A linked plasma membrane (PM) cholesterol availability in CD4 T cells to systemic metabolism. Aster-A was recruited to the PM during T cell receptor (TCR) activation, where it facilitated the removal of accessible cholesterol. Loss of Aster-A increased cholesterol accumulation in the PM, which enhanced TCR nanoclustering and signaling. Aster-A associated with stromal interaction molecule 1 (STIM1) and negatively regulated calcium (Ca²⁺) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (T_H17) phenotype and stimulated interleukin-22 production, which reduced intestinal fat absorption and conferred resistance to diet-induced obesity. These findings delineate how immune cell membrane homeostasis links to systemic physiology.

PubMed Disclaimer

Update of

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption.
Gao Y, Kennelly JP, Xiao X, Whang E, Ferrari A, Bedard AH, Mack JJ, Nguyen AH, Weston T, Uchiyama LF, Lee MS, Young SG, Bensinger SJ, Tontonoz P. Gao Y, et al. bioRxiv [Preprint]. 2024 Mar 11:2024.03.08.584164. doi: 10.1101/2024.03.08.584164. bioRxiv. 2024. Update in: Science. 2025 Oct 9;390(6769):eadt4169. doi: 10.1126/science.adt4169. PMID: 38559079 Free PMC article. Updated. Preprint.

Comment in

A tripartite alliance for dietary fat absorption.
Burkhardt R, Ecker J. Burkhardt R, et al. Science. 2025 Oct 9;390(6769):128-129. doi: 10.1126/science.aeb5717. Epub 2025 Oct 9. Science. 2025. PMID: 41066588

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Atypon
- Ovid Technologies, Inc.
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

T cell cholesterol transport links intestinal immune responses to dietary lipid absorption

Affiliations

T cell cholesterol transport links intestinal immune responses to dietary lipid absorption

Authors

Affiliations

Abstract

Update of

Comment in

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous