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.