Alan Brash, PhD
Professor of Pharmacology, Vanderbilt University

Yuxiang Zheng, PhD
First author of the Journal of Biological Chemistry paper
Post-doctoral fellow, Department of Systems Biology, Harvard University, Boston MA

Christoper P. Thomas PhD
visiting Marie Curie Scholar
Home institute: Cardiff University

Alan Brash, PhD

Recently, a Vanderbilt University team headed by Alan Brash, PhD made a connection between a genetic cause of ichthyosis and the dietary requirement for certain lipids known as essential fatty acids (EFA).  The work explains why, in healthy skin, the essential fatty acid cannot be replaced by other lipids and why its oxidation is important in maintaining a normal skin barrier.

The background to this story begins over 80 years ago, when man-and-wife biochemists George and Mildred Burr discovered the dietary requirement for lipids they named “essential fatty acids" (EFA). They carefully adjusted diets to exclude a type of fatty acid called linoleic acid, which they identified as the primary EFA. Importantly, the Burrs noted the symptoms of a dietary deficiency of EFA, and one of the most obvious was a dry scaly skin.

Scaly skin!….might EFA have something to do with the genetic diseases of ichthyosis? Indeed, this is where one of the genetic causes of ichthyosis comes in.  Among the genes identified with mutations in ichthyosis patients are two related genes named ALOX12B and ALOXE3. These two genes produce enzymes called lipoxygenases (LOX). LOX enzymes oxidize particular lipids – they oxidize only EFA.

So, you need both EFA and the LOX enzymes for healthy skin, but why are they necessary for skin barrier function? Linoleic acid, the primary EFA in the outer epidermis, is attached to another lipid called ceramide. The Vanderbilt team found that oxidation of this EFA by the LOX enzymes is required to release the ceramide for subsequent chemical bonding to proteins. This is a key event in sealing the epidermal water barrier. “Knockout” mice lacking one of the LOX enzymes were unable to oxidize the EFA, they had almost no protein-bound ceramide in the epidermis, and they showed a severe epidermal barrier defect that would lead to ichthyosis.

Are there implications for the treatment of ichthyosis in these findings? Yes, there are, although dietary supplementation with linoleic acid is not one of them! There is plenty of linoleic acid from many sources in a balanced diet, and being deficient is almost unheard of in our society. What is more likely is that new synthetic oxidized lipids formed from linoleic acid may have promise for topical treatment of LOX-related ichthyosis, or it may prove beneficial to treat skin with the “released” ceramide. Finding which lipids are linked with a specific genetic cause may make it possible to tailor topical treatments for each individual.

The results of this study, with first author Yuxiang Zheng, and Christopher Thomas, PhD, visiting Marie Curie Scholar, were reported in a “Best of the Year” paper in 2011 in the Journal of Biological Chemistry. Researchers who collaborated with the Vanderbilt team were Dr. David Beier of Harvard University and Dr. Peter Elias of the University of California, San Francisco. The work was funded by the Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and of Child Health and Human Development (NICHD) of the NIH.