Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease causing dry and itchy skin and, ultimately, skin lesions. AD has a strong genetic component; with the children of the suffering parents at a twofold increased risk of developing the condition. 

Genetic risk loci and epigenetic modifications reported in AD occur in genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors, as environmental triggers also play a crucial role. 

AD causes epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system, and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, like ceramides and free fatty acids. 

A recent review describes the lipid abnormalities observed in the epidermis and blood of AD patients and evaluates their primary role in eliciting an inflammatory response.

AD causes inflammation by activating keratinocytes (KCs), Langerhans cells (LCs) and inflammatory dendritic epidermal cells (IDECs), emphasizing the key role of lipids in AD pathogenesis. Thus, it is relevant to hypothesize that AD is largely a lipid metabolism disorder maturing into an inflammatory disease due to genetic susceptibility in immunogenic genes. 

To date, no genome-wide association studies have shown the susceptibility loci in lipid metabolism in AD, proving that abnormalities in lipid metabolism are induced by genetic susceptibility in genes unrelated to lipid metabolism and/or by environmental factors. Ovo-like transcriptional repressor 1 (OVOL1) might be the missing link between filaggrin (FLG) deficiency and lipid metabolism abnormality in AD. Indeed, OVOL1 regulates the FLG expression, and a recent study (in OVOL1 knock-out mice with induced psoriasis-like inflammation) shows that lipid metabolism is the most altered metabolic pathway, with a significant increase in peroxisome proliferator-activated protein δ (PPAR-δ). 

Pavel et al have recently reported a key role of PPAR-δ signaling in the pathogenesis of AD and potentially of psoriasis by upregulating peroxisomal ß-oxidation via acyl-CoA oxidase (ACOX1) that causes shortening of stratum corneum lipid species, thus initiating or maintaining epidermal barrier impairment in AD. Hence, environmental factors or single nucleotide polymorphisms in nonimmunological genes such as OVOL1 might start a cascade of events causing major lipid metabolism disturbances and epidermal barrier weakening, further creating a favorable milieu for AD development in patients with susceptibility loci in immunogenic genes. Other susceptibility loci like FLG might be involved in causing dry skin and, in turn, itch. However, they might not be sufficient to initiate AD but must combine with other skin abnormalities to become relevant permissive factors, particularly in disease progression.

Source: Pavel P, Blunder S, Moosbrugger-Martinz V, et al. Atopic dermatitis: the fate of the fat. Int J Mol Sci. 2022;23(4):2121.