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

Abstract

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.

Transcriptome-Wide Profile of 25-Hydroxyvitamin D3 in Primary Immune Cells from Human Peripheral Blood

“…However, only the genes MYLIP and ABCG1 were shown to be specifically regulated by 10,000 nM 25(OH)D 3 . Interestingly, both genes are involved in cholesterol transport and are known to be regulated by the nuclear receptor LXR (liver X receptor) [52][53][54] but had not been reported as VDR targets. Moreover, vitamin D metabolites, including 25(OH)D 3 , have been shown to activate LXR [55], i.e., the specific regulation of MYLIP and ABCG1 may be mediated rather by LXR than by VDR.…”

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies

“…It has also been shown to disrupt lysosomal membranes; therefore, hydroxychloroquine could also mediate its effects in AIRDs by modifying lipid raft–mediated immune cell signaling, which can in turn modulate immune cell function (refs. 9 , 68 , and Figure 1A ).…”

“…Immune cell surface receptors (including T cell and B cell receptors and costimulatory molecules) reside within lipid rafts and facilitate appropriate cell signaling in response to antigen or other cellular ligands (refs. 7 – 9 and Figure 1, A–C ). Lipid rafts are altered in SLE, in which an increase in both cell membrane glycosphingolipids and cholesterol attributable to increased cellular lipid synthesis is associated with increased T cell and B cell receptor signaling and ultimately activation and inflammation ( 10 , 11 ).…”

“…Recently, IFNs were shown to have differential effects on membrane cholesterol metabolism in macrophages, including downregulation of cholesterol biosynthesis ( 153 , 154 ); this effect was not observed with TNF-α, IL-1β, or IL-6, suggesting that new therapies such as anifrolumab (anti–type I IFN receptor antibody) could have effects on both systemic (hepatic) and local (immune cell) lipid metabolism. Changes in immune cell lipid metabolism can also influence cell signaling via changes in lipid rafts ( 9 , 68 ). By binding membrane CD20, rituximab induces its translocation to lipid rafts, which is crucial, under some conditions, for induction of B cell apoptosis and can be prevented by disruption of lipid rafts by cholesterol depletion ( 155 ).…”

“…This included T cell receptor signaling and function and anti-dsDNA antibody production by autologous B cells ( 10 , 177 ). Interestingly, elevated glycosphingolipid levels in SLE T cells were associated with the increased expression of the LXR master lipid transcriptional regulator, which directly modulates enzymes involved in glycosphingolipid synthesis ( 9 ). Whether supplementation with compounds targeting LXR could further modulate lipid rafts and AIRD drug efficacies remains to be explored.…”