Key “lipid transporter” for skin barrier integrity identified

MFSD2A is required for the uptake of LPCs containing linoleic acid (LPC18:2) from the blood for normal development of the epidermis. The absence of MFSD2A leads to increased skin inflammation and thickening of the epidermis. Photo by: Bernice Wong

Researchers at Duke-NUS Medical School in Singapore have pinpointed a lipid transporter that enables epidermal cells to import key fatty acids from the bloodstream, a mechanism they say is critical for preserving skin barrier integrity in health and disease.

In a paper in the Proceedings of the National Academy of Sciences, the team determined the transporter MFSD2A mediates uptake of lysophosphatidylcholines (LPCs) into the epidermis, supplying linoleic acid and other phospholipids needed for barrier maintenance and repair. The finding refines the current understanding, which has largely emphasized dietary linoleic acid alone as a determinant of epidermal lipid homeostasis.

“What makes this discovery exciting is that it shows the health of the epidermis relies on the uptake of phospholipids from the blood,” said Professor David Silver, deputy director of the Cardiovascular & Metabolic Disorders Signature Research in a press release. “While it is established that linoleic acid from dietary sources is important, our findings indicate that LPCs support the health and renewal of skin cells by serving as a key source of phospholipid and linoleic acid.”

The epidermis has a sustained demand for lipids, particularly linoleic acid, to support cornified envelope formation and stratum corneum function. To examine whether plasma-derived phospholipids contribute to this demand, the investigators used tissue analysis, gene expression profiling, lipidomics, and human keratinocyte culture models to track how epidermal cells acquire and process LPCs.

They found that epidermal deletion of MFSD2A in pre-clinical models produced a phenotype of barrier disruption, with inflammation and structural damage, despite adequate dietary linoleic acid intake. Lipid profiling showed depletion of linoleic acid–containing species and other key epidermal lipids, indicating that LPC transport via MFSD2A is required to maintain a normal lipid milieu.

MFSD2A expression was also reduced in the outermost epidermal layers of patients with eczema and autoimmune skin disease such as psoriasis, raising the possibility that impaired LPC uptake contributes to disease chronicity by limiting effective barrier repair.

The findings have potential therapeutic implications for inflammatory skin conditions such as eczema and psoriasis. “Our findings suggest that ensuring adequate uptake of LPCs could lead to new and more effective treatments to support skin repair in certain inflammatory conditions,” said Dr. Alvin Chua, clinical associate professor at Duke-NUS Medical School and co-author from the Department of Plastic, Reconstructive & Aesthetic Surgery at Singapore General Hospital.