ZKKL Academic Sharing | Recent Advances in Research on the Effects of Epidermal Intercellular Lipids and Lamellar Bodies on the Skin’s Permeability Barrier

Article reprinted from: Chinese Medical Abstracts – Dermatology

Authors: Chao Chang, Hua Wei, Li Li

[Abstract] Intercellular lipids and lamellar bodies, which mediate lipid transport, constitute the structural basis of the skin’s permeability barrier; these lipids primarily include ceramides, cholesterol, and free fatty acids. During keratinocyte differentiation, lamellar bodies play a crucial role in transporting lipids from the granular layer to the stratum corneum. When the skin barrier is disrupted, lamellar bodies and intercellular lipids contribute to its repair. Consequently, exogenous lipid mixtures can help restore skin barrier function.

[Keywords] Epidermal intercellular lipids; lamellar bodies; permeability barrier

Epidermal lipids and lamellar bodies, which participate in lipid transport, constitute the structural basis of the skin’s permeability barrier. Epidermal lipids can be classified into two categories: first, intercellular lipids, which are structural lipids that contribute to epidermal metabolism and play a crucial role in regulating skin permeability; second, sebum, synthesized and secreted by the sebaceous glands, which is a free‑form lipid and exerts adverse effects on both the structure and function of the skin’s permeability barrier. This review provides an overview of how intercellular lipids and lamellar bodies influence the skin’s permeability barrier.

1. Composition and Functions of Intercellular Lipids

The epidermis is divided, from deep to superficial, into the basal layer, the spinous layer, the granular layer, and the stratum corneum. The physical barrier is primarily located in the stratum corneum and plays a crucial role in regulating the permeation of substances between the inside and outside of the epidermis; for this reason, it is also referred to as the “permeability barrier.” In recent years, numerous studies have demonstrated that intercellular lipids in the stratum corneum consist of approximately 50% ceramides, 25% cholesterol, 15% free fatty acids, and trace amounts of phospholipids and other lipids.

1.1 Ceramide It is an important component of intercellular lipids, a sphingolipid with sphingosine as its backbone, in which the amino group of sphingosine is linked to a fatty acid via an amide bond. Ceramides play a crucial role in regulating epidermal physiological functions and skin bioactivity. The distribution of acyl chain lengths in ceramides can influence the packing and density of lipid bilayers, thereby affecting barrier function. Studies have shown that naturally occurring ceramides typically possess 18‑carbon acyl chains, whereas artificially synthesized ceramide analogs with 4‑ to 8‑carbon acyl chains exhibit permeation-enhancing effects up to 10.8 times greater than those of 6‑carbon analogs, indicating that short‑chain ceramides may compromise skin barrier integrity. Research by Skolova et al. further confirmed that short‑chain ceramides (12‑carbon) with shorter acyl chains (2‑, 4‑, and 6‑carbon) are more likely to disrupt skin barrier function compared to natural ceramides (18‑carbon). Therefore, long‑chain ceramides are essential for maintaining normal skin barrier function. The ceramide content in the stratum corneum steadily declines with age. A reduction in ceramide levels can lead to abnormal skin functions; for instance, dry lesions in patients with pruritic dermatoses often show significantly lower ceramide levels than those in healthy skin.

1.2 Cholesterol It is the principal steroid in the stratum corneum; compared with other tissues, the skin’s stratum corneum contains abundant cholesterol sulfate, which plays a crucial role in regulating the aggregation and desquamation of keratinocytes. Cholesterol sulfate serves as a substrate for steroid sulfatase, and mutations in the steroid sulfatase gene can give rise to X-linked recessive ichthyosis.

1.3 Free Fatty Acids In the stratum corneum, straight-chain free fatty acids with carbon chain lengths greater than 20 are predominant; like cholesterol sulfate, both are lipids bearing charged ionizable groups, and thus are thought to contribute to the formation of the lipid bilayer structure. Moreover, the secretion of free fatty acids is closely linked to epidermal pH: the ionized forms of these fatty acids drive pH changes, helping to maintain the skin’s pH within the range of 4.0–5.5. By modulating the lateral organization of the membrane, the stratum corneum’s pH can regulate the physical properties and stability of the lipid bilayer. Deprotonated free fatty acids influence inter‑lipid interactions—such as the tension within lipid domains—potentially leading to defects in the connections between these domains, thereby compromising the barrier function and resulting in passive permeation.

2. Intercellular Lipids and Disease

2.1 Psoriasis In the skin lesions of psoriasis patients, the levels of long-chain ceramides bound to free fatty acids and of ceramides containing 4-hydroxy‑dihydrosphingosine, as well as sphingomyelin, are lower than in normal skin; however, the total ceramide content remains unchanged. This suggests that the impact of reduced ceramides on the skin barrier may not stem from a decrease in overall quantity, but rather from an imbalance in the relative proportions of different ceramide species.

2.2 Atopic Dermatitis Ceramides are reduced in both lesional and non-lesional skin of patients with atopic dermatitis, with the most pronounced decrease observed in ceramide‑1. Moreover, the ceramide profiles differ between these two skin compartments: while lesional skin shows a reduction in ceramides containing α‑hydroxy fatty acids and an increase in ceramides containing sphingosine, the opposite pattern is seen in normal skin.

3. The structure of lamellar bodies and their role in intercellular lipids

3.1 Structure Lamellar bodies are located in the epidermis; they are ovoid in shape and consist of bilayered membrane‑bound organelles arranged in a circular pattern, measuring approximately 0.2 μm × 0.3 μm. They are secretory structures that arise during keratinocyte differentiation, first appearing in the upper spinous layer and progressively migrating upward into the granular layer, where their numbers increase markedly. Lamellar bodies are highly complex secretory organelles that contain a diverse array of lipids, enzymes, and proteins.

3.2 Effects on Inter-Cellular Lipids Lamellar bodies play a crucial role in transporting lipids from the granular layer to the stratum corneum. Studies have identified ABCA as a lipid transporter, with ABCA12 being indispensable for the accumulation of glucosylceramide within lamellar bodies. Loss-of-function mutations in ABCA12 impair the synthesis of normal lamellar body components and the formation of the extracellular bilayer lipid membrane. Research on ichthyosis vulgaris has shown that defective ABCA12 function leads to impaired lipid transport in the stratum corneum, resulting in this condition; thus, ABCA12 is considered a key transporter involved in keratinocyte lipid trafficking. Scholars including Akiyama suggest that partial loss-of-function mutations in ABCA12 are associated with the development of type 2 lamellar ichthyosis. However, the mechanisms by which cholesterol and phospholipids are transported into lamellar bodies remain unclear.

4. The effects of lamellar bodies and intercellular lipids on the skin barrier

When mechanical damage—such as repeated application of adhesive tape or repeated local cleaning with solvents or detergents—leads to acute disruption of the skin barrier, lamellar bodies and lipids mount a rapid response to restore barrier function.

4.1 Lamellar bodies When the skin barrier is acutely disrupted, granular-layer cells rapidly secrete and assemble precursor lamellar bodies, leading to a short-term reduction in their numbers and inhibiting lipid transport, thereby achieving initial repair of the stratum corneum’s lipid membrane. Subsequently, newly formed lamellar bodies emerge in the granular layer and promptly exert their function until the permeability barrier is restored. Studies have shown that within the first 15–30 minutes after barrier disruption, the lipid bilayer structure in the upper stratum corneum is compromised, with numerous gaps appearing; meanwhile, the preexisting lamellar bodies in the upper granular layer swiftly release and transport corresponding substances, which adopt a folded‑sheet morphology to fill the intercellular spaces of keratinocytes, resulting in substantial consumption of these lamellar bodies. Approximately 30 minutes later, newly synthesized lamellar bodies begin to appear in the granular layer, secreting large amounts of lipids, proteins, and other components to participate in barrier repair until its function returns to normal.

4.2 Ceramide Sphingolipids constitute the structural backbone of ceramides. During acute disruption of the skin barrier, the synthesis of sphingolipids in the epidermis is upregulated, and the activity of serine palmitoyltransferase—enzymatic machinery involved in sphingolipid biosynthesis—is also enhanced. Glucosylceramides are the predominant sphingolipids in lamellar bodies and are synthesized from ceramide by the action of glucosylceramide synthase. The activity of glucosylceramide synthase is primarily localized to the upper layers of the epidermis. Studies have shown that, under conditions of acute barrier disruption, the activity of glucosylceramide synthase does not increase. However, topical application of P4, which inhibits glucosylceramide synthase activity, slows the repair of the acutely compromised skin barrier, indicating that glucosylceramides play a critical role in maintaining the skin’s permeability barrier. In animal experiments conducted by Jennemann et al., mice lacking glucosylceramide synthase died shortly after birth and exhibited abnormalities in lamellar body formation and stratum corneum architecture, suggesting that deficiency of this enzyme leads to impaired skin barrier function.

4.3 Cholesterol During acute disruption of the skin barrier, cholesterol synthesis is upregulated. In the cholesterol biosynthetic pathway, the activity of β‑hydroxy‑β‑methylglutaryl‑CoA reductase (HMG‑CoA reductase) increases at both the protein and RNA levels, and the expression of farnesyl pyrophosphate synthase and squalene synthase is also elevated. HMG‑CoA reductase activity begins to rise 15 minutes after acute barrier disruption, peaks at 2.5 hours, and returns to baseline by 15 hours. In animal studies, mice lacking 3β‑hydroxysterol‑Δ24‑reductase—a enzyme that catalyzes the conversion of desmosterol to cholesterol—exhibit substantial accumulation of desmosterol in their epidermis. Due to abnormalities in the skin barrier, these mice die shortly after birth, further underscoring the critical role of cholesterol in maintaining skin integrity. Moreover, defects in other terminal steps of cholesterol biosynthesis are also associated with cutaneous disorders, highlighting the indispensable contribution of cholesterol synthesis to skin barrier function. ABCA1, a membrane transporter, regulates intracellular cholesterol levels: increased ABCA1 expression elevates cellular cholesterol, whereas reduced ABCA1 expression lowers it. Upon acute disruption of the skin barrier, ABCA1 expression declines, leading to a reduction in intracellular cholesterol and facilitating the efflux of excess cholesterol to support the restoration of the permeability barrier.

4.4 Fatty Acids When the skin barrier is acutely disrupted, the synthesis of fatty acids increases. The fatty acids in the stratum corneum are predominantly long-chain; this structural feature influences the activation and/or expression of enzymes involved in barrier repair. Studies have shown that animals lacking ELOVL4 exhibit severe defects in skin barrier function and die shortly after birth. Downregulation of ELOVL4 shortens the chain length of N‑acyl lipids, depriving ceramides of long‑chain fatty acids, which in turn leads to impaired skin barrier integrity and a reduction in the lipid lamellae of the stratum corneum. Thus, long‑chain fatty acids play a critical role in maintaining normal skin barrier function.

5. Topical lipid mixtures improve skin barrier function.

Topically applied lipid mixtures are broadly categorized into two types. The first comprises non‑physiological lipids, such as mineral oil, petroleum jelly, lanolin, and beeswax. These do not enter lamellar bodies to participate in their metabolic pathways; instead, they intercalate between corneocyte gaps, forming an impermeable barrier that prevents the loss of water and electrolytes. While these lipids can rapidly restore some aspects of skin barrier function, they fail to fully normalize barrier integrity because they do not address the underlying skin abnormalities. The second category consists of physiological lipids, including ceramides, cholesterol, and free fatty acids. These lipids can traverse the stratum corneum to reach granular layer cells and, together with endogenously produced lipids, help repair a disrupted skin barrier. Consequently, formulating physiological lipid blends according to precise ratios is crucial; even minor imbalances can adversely affect both the structure of lamellar bodies and the functional integrity of the skin barrier. Under different cutaneous physiological and pathological conditions, it is essential to prioritize supplementation of the lipids that are most deficient. For instance, in aged, naturally senescent skin, cholesterol synthesis declines markedly; therefore, therapies incorporating cholesterol or cholesterol‑rich lipid formulations yield favorable outcomes, whereas products dominated by fatty acids may impede barrier repair. In patients with atopic dermatitis, the primary deficiency lies in ceramides; thus, ceramide‑based or ceramide‑enriched products generally outperform cholesterol‑dominated formulations. Studies have shown that, when repairing physically damaged skin—such as that caused by adhesive tape—short‑term use of ceramide‑rich physiological lipid barrier‑repair agents provides superior protective effects compared with cholesterol‑rich alternatives. In certain situations, combining non‑physiological and physiological lipids can also be advantageous. Since physiological lipids require cellular uptake and metabolic processing before exerting their reparative effects, a time lag may occur. By co‑administering non‑physiological lipids, an immediate, non‑permeable barrier can be established, thereby preventing further loss of water and electrolytes.

6. Conclusion

In summary, epidermal intercellular lipids and lamellar bodies, through a series of complex and highly regulated biochemical processes, play a crucial role in maintaining the skin’s permeability barrier function. Clinically, when treating skin barrier dysfunction caused by reduced intercellular lipids, the application of exogenous lipid mixtures has proven to be both reliable and effective. Therefore, for patients with deficiencies in specific lipid components, it is essential to develop and implement more targeted topical lipid formulations.

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