The nuclear hormone receptor (NHR) liver X receptor β (LXRβ) has been highlighted as a possible candidate for involvement in ageing by several recent findings. LXRβ is the closest human homologue to the longevity-associated gene daf-12 in the nematode worm and LXRβ haplotypes have been associated with longevity at old ages in a longitudinal human genetic study. Whilst LXRβ is primarily responsible for mediating the effects of LXR oxysterol ligands throughout most of the body, LXRβ is the primary mediator of these effects uniquely in the skin. In this thesis studies are presented on the expression of LXRβ mRNA and protein in human skin, comparing young vs intrinsically (chronologically) aged skin, photoprotected vs photoaged (dueto ultraviolet radiation exposure) skin and untreated vs retinoid-treated photoaged skin, retinoid treatment being a primary clinical intervention for photoageing. In situ hybridisation and quantitative polymerase chain reaction (qPCR) were used to identify LXRβ mRNA and immunofluorescence was used to identify LXRβ protein. These comparisons revealed that both the mRNA and protein expression of LXRβ are highly stable throughout the ageing, photoageing and retinoid treatment of human skin. Previous authors have identified overlap between microarray gene expression datasets in the LXRβ-/- mouse and in normal human skin ageing. In these studies comparisons of different microarray datasets have been conducted with the finding that LXR agonist treatment of mice produces gene regulation patterns with significant overlap to that seen in both ageing and calorie restriction in mice (binomial test; p<0.001). Furthermore, when considering the genes commonly regulated in LXR agonist treatment and ageing, 73% of these genes are regulated in opposite directions. Conversely, when considering genes commonly regulated in LXR agonist treatment and calorie restriction, 70% of these genes are regulated in the same direction. These findings suggest that LXR agonists have possible benefit as ageing therapies, perhaps due to stimulating a calorie restriction-like response. Further work would be necessary to confirm these properties of LXR agonists and to define the roles of LXRβ in the ageing and normal function of human skin.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:529235 |
| Date | January 2010 |
| Creators | Ford, Christopher |
| Contributors | Watson, Rachel ; Griffiths, Christopher |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-nuclear-hormone-receptor-liver-x-receptor-beta-in-skin-ageing(60c2637f-3bda-4606-9c1a-0bd405e34dfb).html |
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