Healing fats of the skin: the structural and immunologic roles of the ω-6 and ω-3 fatty acids (original) (raw)

Introduction

Interest in the use of dietary fats to treat skin disease is marked by the historic study of Burr and Burr in 1929,1, 2 where rats fed a diet devoid of all fat experienced growth retardation, reproductive failure, and a scaling erythematous skin eruption with increased transepidermal water loss. Clinical manifestations diminished when the diet was supplemented with linoleic and α-linolenic acids. Similarly, one of the investigators from these early experiments found he could rid his hand dermatitis by consuming these polyunsaturated fatty acids (PUFAs). Originally referred to as vitamin F, these fats soon came to be known as the essential fatty acids (EFAs), because humans lack the enzymes necessary for their synthesis.

These original works, as well as other early studies, have been criticized because a distinction was not drawn between supplementation with ω-6 (linoleic acid) or ω-3 (α-linolenic) fatty acids.3 Differentiating between the two is important, because their roles, as we have now come to understand more clearly, are distinct—linoleic acid and its products serve as structural precursors for the important stratum corneum ceramides, and α-linolenic derivatives serve as immune modulators. We have just begun to recognize the sophisticated contribution of the PUFAs in skin disease through these and other structural and immunologic roles.

As we shall discuss, linoleic acid (LA) and its derivatives play a central role in the structure and function of the stratum corneum permeability barrier, defects of which are most notable in atopic dermatitis. Derivatives of α-linolenic acid (ALA) can modulate the immune response of the epidermis by influencing T lymphocytes, acting on Toll-like receptors (TLRs), and activating caspase cascades that influence many inflammatory dermatoses, including acne vulgaris, psoriasis, atopic dermatitis, systemic lupus erythematosus, and skin cancer. Finally, the ω-3s are ligands for an important class of transcription factors, the peroxisome proliferator-activated receptors (PPARs), which are important in lipid metabolism, sugar homeostasis, and insulin sensitization as well as inflammation, immune regulation, and skin barrier homeostasis. They also show promise as natural options for treating inflammatory skin disease and skin carcinogenesis, including melanoma.

Section snippets

PUFA terminology, metabolism and dietary homeostasis

LA (18:2ω6) and ALA (18:3ω3) represent the parent fats of the two main classes of PUFAs: the ω-6 (n-6) and the ω-3 (n-3) fatty acids, respectively. LA and ALA both give rise to other long-chain fatty acid derivatives and a host of other lipid mediators, including prostaglandins, leukotrienes, and lipoxins by way of a shared set of enzymes (Figure 1).

LA is found in the oils of safflower, grape seed, poppy seed, sunflower, hemp, corn, wheat germ, cottonseed, and soybean. Many of these oils are

LA and the stratum corneum permeability barrier

LA is the most abundant fatty acid in the epidermis. Importantly, it is also the precursor to ceramides, a major component of the extracellular lipid matrix that forms the stratum corneum permeability barrier (SCPB). There are essentially three components of the SCPB: the extracellular lipid matrix, the cornified envelop, and dense keratin fibrils aggregated by filaggrin. The extracellular lipid matrix is composed of 50% ceramides, 25% cholesterol, and 15% free fatty acids.9 Lipids, enzymes,

Immune-modulating roles of ω-3 fatty acids in the epidermis and skin disease

DHA and EPA are not major constituents of the epidermis, which is likely a reflection of insufficient dietary consumption or increased cellular utilization. Unlike LA, which plays a major structural role in the epidermis and SCPB, ω-3 fatty acids appear to play an immune-modulating role. EPA has been shown to reduce the expression of intercellular adhesion molecule-1,59 reduce T-lymphocyte proliferation, and dampen delayed-type hypersensitivity.60 Diets supplemented with fish oil can lead to

Introduction to the PPARs

Ligands for the PPARs are emerging as valuable treatments for many diseases, including skin disease. DHA and EPA are natural ligands for these receptors. Synthetic ligands, such as the thiazolidinediones, have been used in psoriasis with success.85 There are three PPAR isoforms: PPAR-α, PPAR-β/Δ, and PPAR-γ. They are members of the nuclear receptor family that partner with the retinoic acid X receptor to fulfill their functions. Their primary role has been in cardiovascular medicine and

TLRs and ω-3 fatty acids

The TLRs are a fairly recently identified group of receptors that are present on many cells, including keratinocytes, monocytes, Langerhans cells, dermal dendritic cells, and intestinal epithelial cells. The TLRs are involved in the first-line recognition of pathogens. They are pattern-recognition receptors that recognize certain pathogen-associated molecular patterns expressed by microbes. TLRs communicate signals of tolerance from recognized commensals or, when danger is sensed, elicit

Conclusions

The mechanisms of the nutritional deficiency dermatosis originally recognized by Burr and Burr1, 2 are becoming more fully understood as the diverse and elaborate roles of the PUFAs are elucidated. Furthermore, PUFAs are proving to be essential to healthy skin and aid in the healing of diseased skin.

A fatty acid profile can help identify patients with suboptimal fatty acid concentrations. Absolute fatty acid concentrations, ω-6:ω-3 ratios, and mead acid levels—a marker of essential fatty acid