What is epilipidome?

What is epilipidome?

What is epilipidome?

What are skin lipids?

The keratinocyte (KC) lipidome consists mainly of phospholipids, cholesterol, and triacylglycerides. The keratinocyte turnover time (differentiation of living keratinocytes into dead corneocytes), which constantly renews the epidermal barrier, drastically changes the lipid composition of these cells several times throughout the process. The granular layer of the epidermis (the last living layer of the epidermis) contains cells with lamellar bodies containing glucosylceramides, phospholipids, and sphingomyelin, which are further metabolized to stratum corneum lipids, mixtures of free fatty acids (FFA), cholesterol, and ceramides. SC lipids form a lipid matrix between the corneocytes that arises from terminal differentiation. Some of the matrix lipids also come from sebum [a mixture of triacylglycerols (TAGs), wax, squalene, and free fatty acids (FFAs)], produced by holocrine sebaceous glands (whole cells transform into a secretion and detach from the glandular epithelium).


The cutaneous lipidome (all skin lipids) has a variety of cellular functions, including:

  • building blocks of membranes,
  • energy storage,
  • signal mediators,
  • protective functions (co-creating a hydro-lipid coat, protection against pathogens, protection against mechanical injuries, etc.)
  • regulation of permeability, including TEWL (Transepidermal Water Loss) reducing

The functions of lipids result from their structural diversity. The complexity of the lipidome is further expanded by enzymatic and non-enzymatic modifications, oxidation, nitration, sulfation, and halogenation. Modified lipids are not “waste” but compounds that actively regulate complex biological processes. This new level of structural, functional, and regulatory complexity of the lipidome is called an epilipidome. Modified lipids are essential as key elements in metabolism regulation, function, and cell death.

Most of the biological consequences of epilipidomic modification occur in the epidermis’ living layers, although SC lipids are also susceptible to modification. Some of the changes are regulated by the reactive oxygen species ROS (e.g., squalene oxidation), and others depend on enzymatic cascades, e.g., the formation of a lipid envelope in which hydroxyceramides are esterified to corneocyte proteins by specific transglutaminases.


The most studied skin lipid modifier is solar radiation and its wavelength bands. The effect of UVR (Ultra Violet Radiation) on human skin is wavelength dependent and can cause:

  • acute inflammation,
  • immunosuppression,
  • cell death (a combination of UV radiation with photoactive drugs to kill cancer cells or the immune system).

UVR can cause enzymatic as well as non-enzymatic lipid modification. UVA with a wavelength of 320–400 nm and shorter oxidizes lipids without enzymes by free radical mechanisms. Cholesterol, phospholipids, free fatty acids, and squalene are targets for non-enzymatic oxidation and yield bioactive products. Enzymatic synthesis of oxidized lipids, mainly eicosanoids EPA and polyunsaturated fatty acids PUFA, results from UV activation of phospholipases, lipoxygenases, and cyclooxygenases.

Hundreds of enzymatic and non-enzymatic oxidation products can be distinguished in human fibroblasts and keratinocytes immediately after UV irradiation (e.g., oxidized phosphatidylcholine, phosphatidylcholine hydroperoxides, hydroxides, etc.). These products are potent inducers of various mechanisms and signaling pathways that can be attributed, among other things, to the protective, pro-resolution spectrum of activity of oxidized phospholipids.

Dietary fatty acid consumption influences the systemic and skin composition of FFAs and the composition of the phospholipids to which these fatty acids are esterified. It also affects the potential enzymatic and non-enzymatic oxidation products formed after exposure to UV radiation. Supplementation with EPA and subsequent exposure to UV radiation led to a shift of the UVA-induced eicosanoids towards the EPA metabolites (prostaglandin E3 and 12-hydroxy-eicosapentaenoic acid), which show less pro-inflammatory activity.

Both the type of UV-induced lipid signaling mediator and the ability of the cell to limit peroxidation may determine the epilipidomic effect on the regulation of UV-mediated inflammation. The researchers noticed that only in cells deficient in Nrf2 (a transcription factor with protective functions), increased susceptibility to oxidation led to increased expression of inflammatory markers.

UV can enzymatically generate the platelet-activating factor PAF, although PAF-like lipids can also be generated by the action of free radicals on phospholipids. PAF and PAF-like lipids induce both acute inflammatory and delayed immunosuppressive UV effects and potentially elicit systemic signals by releasing microbubbles (exosomes) from corneocytes.

The UV modifications also include sebum. Squalene hydroxides generated by UV exposure have been identified in vitro and in vivo. Because squalene is the main component of the epidermal surface lipids, its peroxidation products, including squalene hydroxides and reactive aldehydes, are recognized as sensors for metabolic and inflammatory responses to UV radiation. The full spectrum of the immunomodulatory (UV) effects of oxidized squalene and other sebaceous lipids is underway, suggesting that the epidermal inflammasome is a cellular component that senses and transmits inflammatory signals.

The inflammasome is an intracellular, multiprotein complex involved in the innate immune response, responsible for detecting molecular patterns that indicate damage-associated molecular patterns (DAMP) and the pathogen-associated molecular patterns (PAMP), and the production of pro-inflammatory cytokines.


The two major chronic inflammatory skin diseases associated with disorder barrier function, psoriasis and atopic dermatitis AD, affect the composition and sequence of epidermal barrier lipids, the composition of essential epidermal, dermal, and systemic lipids. Epilipidome-related metabolites are regulated and likely affect the disease, although data are still limited.

The first studies using resolvin D1 on patient keratinocytes resulted in a reduction in interleukin synthesis by these cells, indicating that epilipidome mediators, whether applied topically or generated in situ, may be helpful in the treatment of psoriasis. At the same time, the pro-inflammatory components of the epilipidome likely contribute to the inflammation. Resolvin D1 comes from a family of solid lipid mediators derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has anti-inflammatory effects, and promotes the reversal of the inflammatory response back to a non-inflammatory state.

In patients with AD, elevated levels of epilipidome metabolites [lysophosphatidylethanolamine (18:2), thromboxane b2 (TXB2) and 11-, 12-dihydroxyeicosatriene acid (DHET)] have been shown in skin tissue lipid samples. The other research has shown that the ratio of pro-inflammatory mediators to pro-inflammatory mediators regression was increased in patients, significantly oxidized PPAR alpha agonists. Agonists, particularly 12-hydroxy-eicosatetraenoic acid (12-HETE), mediate inflammation and disrupt differentiation in organotypic skin models in AD. Agonism or signaling through prostaglandin receptors, PPARs, and pattern recognition receptors (PRRs) through lipid changes mediated by ROS have been reported.


In prematurely photoaging skin, highly reactive lipid oxidation products and their adducts accumulate. Also, chronological skin aging at the cellular level and aging of cells are similarly associated with lipo-oxidative redox processes, such as the accumulation of ROS in mitochondrial dysfunction and chronic inflammation associated with aging.

The cellular composition of the skin and synthetic and metabolic processes change throughout life, and these changes affect the skin’s lipids and epilipidome. Epilipidomic changes introduce a new autonomic signaling layer for complex exposure-response relationships in cellular stress, aging, and inflammation.

Studies have shown that increased leukotriene production is a feature of senescent fibroblasts that promotes pulmonary fibrosis. Changes in the oxidized phospholipidome characterize aging fibroblasts.

The skin is exposed to temperature fluctuations, which probably influences the dynamics of epilipidomic modifications mediated by enzymes and ROS.

A study of the barrier lipids of acne patients documented that the ceramide types Cer [NH] and Cer [AH] were significantly reduced. This effect was most significant in winter and correlated with the highest rates of trans-epidermal water loss (TEWL). The substantial reduction in ceramides with 18-carbon forms of 6-hydroxysphingosine exemplifies the various consequences of the lipid oxidative modification on the epidermal barrier function.

A study of SC (redox-) lipids from volunteers receiving glucocorticosteroids (GC) showed that the skin barrier damage, which is a side effect of GC therapy, was associated with the reduction of ceramides by the esterified omega-hydroxyacyl chain. Also, anti-cancer chemotherapy can affect cutaneous epilipidome. Chemotherapy produces lipids agonists at the platelet-activating factor receptor PAF (through ROS production), which negatively influencing anti-tumor immunity.

Cigarette smoke (CS) is a lifestyle-related stressor to the skin, and exposure of keratinocytes to CS increases the formation of carbonyl adducts (4-hydroxy-2-nonenal; 4-HNE), possibly due in part to lipid oxidation and PAF-like immunosuppressive lipids.

A novel therapeutic option in treating wounds and inflammations is the application of cold atmospheric plasma CAP, which contains highly dynamic matter, to the diseased tissue. The consequence of such treatment is a massive change in the skin epilipidome. It remains to be investigated whether the changes in skin lipidome will contribute to effective treatment that appears to involve activating the antioxidant response.

In addition to the oxygen-mediated lipid modification of lipids, the epilipidome complexity can be increased by sulfonation of the lipids, nitration and nitroxidation of phospholipids. Recent advances in the accuracy and specificity of mass spectrometry have made it possible to study enzymatic and non-enzymatic modifications of the lipid – the epilipidome – multiplying the diversity of molecules in this class. The skin is an organ that is often exposed to oxidative, chemical, and thermal stress and injuries, and inflammation and is, therefore, an ideal organ for studying the dynamics of the epilipidome, their causes, and biological consequences. Recent studies reveal the loss or enhancement of biological functions due to specific modifications or the sum of lipid modifications. Research suggests an essential role for the epilipidome in the skin’s stress responses and immune regulation.

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