LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes i...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-05, Vol.118 (21), p.1
Main Authors: Waddington, Kirsty E, Robinson, George A, Rubio-Cuesta, Beatriz, Chrifi-Alaoui, Eden, Andreone, Sara, Poon, Kok-Siong, Ivanova, Iveta, Martin-Gutierrez, Lucia, Owen, Dylan M, Jury, Elizabeth C, Pineda-Torra, Inés
Format: Article
Language:English
Subjects:
Adolescent
Adult
Benzoates - pharmacology
Benzylamines - pharmacology
Biological Sciences
Biosynthesis
CD4 antigen
Cell activation
Cell Membrane
Ceramide glucosyltransferase
Cholesterol
Cholesterol - genetics
Cholesterol - immunology
Fatty acids
Female
Gene expression
Glucosyltransferases - genetics
Glycosphingolipids
Glycosphingolipids - biosynthesis
Glycosphingolipids - genetics
Glycosphingolipids - immunology
Hepatocytes
Humans
Immunological Synapses - drug effects
Immunological Synapses - genetics
Immunoregulation
Inflammation
Ligands
Lipid metabolism
Lipid Metabolism - genetics
Lipid Metabolism - immunology
Lipids
Liver X receptors
Liver X Receptors - agonists
Liver X Receptors - antagonists & inhibitors
Liver X Receptors - genetics
Liver X Receptors - immunology
Lymphocytes
Lymphocytes T
Male
Membranes
Metabolic Networks and Pathways - immunology
Metabolism
Middle Aged
Mode of action
Oxysterols - pharmacology
Phospholipids
Signaling
T-Lymphocyte Subsets - drug effects
T-Lymphocyte Subsets - immunology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Transcription
Young Adult
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Summary:The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4 T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2017394118