Cholesterol homeostasis in hair follicle keratinocytes is disrupted by impaired ABCA5 activity

Abstract

The importance of cholesterol in hair follicle biology is underscored by its links to the pathogenesis of alopecias and hair growth disorders. Reports have associated defects in ABCA5, a membrane transporter, with altered keratinocyte cholesterol distribution in individuals with a form of congenital hypertrichosis, yet the biological basis for this defect in hair growth remains unknown. This study aimed to determine the impact of altered ABCA5 activity on hair follicle keratinocyte behaviour. Primary keratinocytes isolated from the outer root sheath of plucked human hair follicles were utilised as a relevant cell model. Following exogenous cholesterol loading, an increase in ABCA5 co-localisation to intracellular organelles was seen. Knockdown of ABCA5 revealed a dysregulation in cholesterol homeostasis, with LXR agonism leading to partial restoration of the homeostatic response. Filipin staining and live BODIPY cholesterol immunofluorescence microscopy revealed a reduction in endo-lysosomal cholesterol following ABCA5 knockdown. Analysis of oxysterols showed a significant increase in the fold change of 25-hydroxycholesterol and 7-β-hydroxycholesterol following cholesterol loading in ORS keratinocytes, after ABCA5 knockdown. These data suggest a role for ABCA5 in the intracellular compartmentalisation of free cholesterol in primary hair follicle keratinocytes. The loss of normal homeostatic response, following the delivery of excess cholesterol after ABCA5 knockdown, suggests an impact on LXR-mediated transcriptional activity. The loss of ABCA5 in the hair follicle could lead to impaired endo-lysosomal cholesterol transport, impacting pathways known to influence hair growth. This avenue warrants further investigation.

Publication DOI: https://doi.org/10.1016/j.bbalip.2023.159361
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
Funding Information: MAP was funded by an institutional studentship from the University of Huddersfield . The authors would like to thanks Nikolaos T Georgopoulos from the University of Huddersfield for provision of materials to finalise the revised manuscript, and co-supervi
Additional Information: Copyright © 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/). Funding & acknowledgements: MAP was funded by an institutional studentship from the University of Huddersfield. The authors would like to thanks Nikolaos T Georgopoulos from the University of Huddersfield for provision of materials to finalise the revised manuscript, and co-supervision of MAP.
Uncontrolled Keywords: Keratinocytes,Hair follicle,Cholesterol,ABCA5
Publication ISSN: 1879-2618
Last Modified: 23 May 2024 07:26
Date Deposited: 06 Jul 2023 08:08
Full Text Link:
Related URLs: https://www.sci ... 0859?via%3Dihub (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-09
Published Online Date: 2023-06-20
Accepted Date: 2023-06-09
Submitted Date: 2022-09-30
Authors: Palmer, Megan A
Dias, Irundika H K (ORCID Profile 0000-0002-6620-8221)
Smart, Eleanor
Benatzy, Yvonne
Haslam, Iain S

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