Alterations of the lipid profile of the stratum corneum have an important role in the pathogenesis of atopic dermatitis (AD) because they contribute to epidermal barrier impairment. However, they have not previously been envisioned as a cellular response to altered metabolic requirements in AD epidermis. In this study, we report that the lipid composition in the epidermis of flaky tail, that is, ft/ft mice mimics that of human lesional AD (ADL) epidermis, both showing a shift toward shorter lipid species. The amounts of C24 and C26 free fatty acids and C24 and C26 ceramides-oxidized exclusively in peroxisomes-were reduced in the epidermis of ft/ft mice despite increased lipid synthesis, similar to that seen in human ADL edpidermis. Increased ACOX1 protein and activity in granular keratinocytes of ft/ft epidermis, altered lipid profile in human epidermal equivalents overexpressing ACOX1, and increased ACOX1 immunostaining in skin biopsies from patients with ADL suggest that peroxisomal β-oxidation significantly contributes to lipid signature in ADL epidermis. Moreover, we show that increased anaerobic glycolysis in ft/ft mouse epidermis is essential for keratinocyte proliferation and adenosine triphosphate synthesis but does not contribute to local inflammation. Thus, this work evidenced a metabolic shift toward enhanced peroxisomal β-oxidation and anaerobic glycolysis in ADL epidermis.
Keywords: AD, atopic dermatitis; ADL, lesional atopic dermatitis; ATP, adenosine triphosphate; Cer, ceramide; CoA, coenzyme A; FA, fatty acid; FFA, free fatty acid; HEE, human epidermal equivalent; IMQ, imiquimod; KC, keratinocyte; KO, knockout; LB, lamellar body; PPAR, peroxisome proliferator–activated receptor; SC, stratum corneum; TEWL, transepidermal water loss; ULCFA, ultra long-chain fatty acid; VLCFA, very-long-chain fatty acid.
© 2021 The Authors.