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Title: Frontiers in the lipid biology of human skin : the role of DGAT1 in skin function and homeostasis
Author: Hinde, Eleanor
ISNI:       0000 0004 5919 5818
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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The skin of mammals contains sebaceous glands (SGs) which are attached to the hair follicle (HF), and their best known function is to release sebum onto the skin surface via the HF canal. It has long been known that these two entities of the pilosebaceous unit are interconnected, but the extent to which the two ‘control’ one another was less clear. The current project set out to investigate the impact of the HF cycle on the SG. It was found that in a depilation- induced HF cycle, SG morphology altered drastically, with an increase in SG area (P<0.001), number of sebocytes (P<0.001), and individual sebocyte area (P<0.001) occurring after HF depilation. In SGs attached to a spontaneously cycling HF, none of the above was observed, indicating that spontaneous HF cycling does not affect SG morphology, whereas anagen induction by depilation is associated with altered SG morphology, likely as a result of HF trauma. Diacylglycerol acyltransferase 1 (DGAT1) is an enzyme known for its role in the production of various lipids. It was previously shown that DGAT1 knockout in mice caused SG atrophy, which was thought to be caused by an increased level of retinoic acid within the skin, which in turn caused atrophy of the gland. The current project aimed to further investigate the role of the DGAT1 enzyme in murine skin. Based on the results of the previous experiments, HF and SG morphology of spontaneously-cycling DGAT1 knockout mice were assessed. It was found that DGAT1 knockout caused delayed HF morphogenesis, altered HF cycling, increased HF length (P<0.001), more acute HF growth angle (P<0.001), increased SG apoptosis(P<0.001), decreased SG lipid content (P<0.001) and dysfunctional lipid droplet formation. The impact of DGAT1 knockout on HF morphology and cycling suggests that DGAT1 knockout causes alterations in the WNT/ beta-catenin signalling pathway, as these processes are highly controlled by this signalling pathway. In order to investigate the role of the DGAT1 enzyme in human HFs, and to investigate the hypothesis that DGAT1 may directly interact with the WNT/ beta-catenin signalling pathway, HFs were organ-cultured in the presence of a pharmacological DGAT1 inhibitor (AZD7687). It was found, at the transcriptional level, that one of the major canonical pathways affected by DGAT1 inhibition in human HFs was the WNT/ beta-catenin signalling pathway. DGAT1 inhibition was found to cause suppression of the WNT/beta-catenin signalling pathway via a down-regulation of a number of WNT/beta-catenin related genes. Overall, these results show that SG morphology is largely dependent upon HF homeostasis, and suggest that the DGAT1 enzyme may possess a previously unknown role, directly impacting the WNT/ beta-catenin signalling pathway.
Supervisor: Paus, Ralf ; Haslam, Iain Sponsor: Biotechnology and Biological Sciences Research Council ; AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Sebaceous Gland ; Hair Follicle ; Diacylglycerol acyltransferase 1