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Publication Detail
Regulation of membrane lipid metabolism and immune cell function by the nuclear receptor LXR
  • Publication Type:
    Thesis/Dissertation
  • Authors:
    Waddington KE
  • Date awarded:
    2018
  • Pagination:
    1, 205
  • Status:
    Unpublished
  • Awarding institution:
    UCL (University College London)
  • Language:
    English
Abstract
Liver X receptors (LXRs) are transcription factors with a critical role in multiple lipid metabolic pathways, and a broad range of effects on inflammatory and immune responses. I hypothesised that LXRs modulate CD4+ T cell function by regulating plasma membrane lipid rafts- highly ordered cholesterol and glycosphingolipid (GSL) enriched regions important for T-cell antigen receptor (TCR) signalling. Importantly, the GSL biosynthesis enzyme UGCG was identified as a novel LXR target gene in multiple human immune cell subsets. In CD4+ T cells, LXR activation with the synthetic ligand GW3965 regulated both cholesterol and glycosphingolipid metabolism, which resulted in reduced plasma membrane lipid order and altered responses to TCR activation. Changes in the kinetics and distribution of membrane lipid order at the immune synapse led to accumulation of TCR-proximal signalling molecule Lck at the synapse periphery. Subsequently, tyrosine phosphorylation of signalling and adapter proteins was altered. Ultimately, this was associated with an altered profile of T cell cytokine production and reduced T cell proliferation. I further hypothesised that LXR signalling may be dysregulated in CD4+ T cells from patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE), since defects in lipid raft-associated signalling have previously been identified in immune cells from SLE patients. Multiple changes in lipid metabolism were detected. However, LXR target gene expression and responses to LXR activation were only modestly perturbed. Instead, IFN response coincided with changes in expression of lipid metabolism genes both ex vivo, and in response to SLE patient serum. In summary, I have uncovered a novel action of LXR that involves modulation of lipid raft-associated cholesterol and GSLs in CD4+ T-cells. This could have important implications in diseases involving dysregulated T cell function including autoimmunity, cancer and atherosclerosis.
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