Epidermal intercellular lipids and lamellar bodies involved in lipid transport are the material basis of the skin permeability barrier, and these lipids mainly include ceramides, cholesterol, free fatty acids and the like. The lamellar bodies formed during the differentiation of keratinocytes play an important role in the transport of lipids from the granular layer to the stratum corneum. When the skin barrier function is disrupted, lamellar bodies and intercellular lipids are involved in the repair of barrier function. Therefore, an exogenous lipid mixture can improve the skin barrier function.
Epidermal lipids and lamellar bodies involved in lipid transport are the material basis for the skin permeability barrier. Epidermal lipids can be divided into two categories: one is epidermal intercellular lipids, which are structural lipids, which are involved in epidermal metabolism and play an important role in regulating skin permeability. The sebum is synthesized and secreted by sebaceous glands. It belongs to free lipids and has an adverse effect on the structure and function of the skin permeability barrier. This article focuses on the effects of intercellular lipids and lamellar bodies on the skin permeability barrier.
The epidermis is divided into a basal layer, a spinous layer, a granular layer and a stratum corneum from the inside to the outside. The physical barrier is mainly located in the stratum corneum, which plays an important role in controlling the penetration of substances inside and outside the epidermis, and is therefore also called the “permeability barrier”. In recent years, a large number of studies have shown that the stratum corneum intercellular lipids are composed of about 50% ceramide, 25% cholesterol, 15% free fatty acids, and very small amounts of phospholipids and other lipids.
1.1 Ceramide is an important component of intercellular lipids
Ceramide is a sphingolipid composed of sphingosine, and the amino group of sphingosine is linked to a fatty acid via an amide bond. Ceramide plays an important role in regulating the physiological functions of the epidermis and the biological activity of the skin. The distribution of acyl chain lengths of ceramides can affect the arrangement and density of lipid membrane lipids to affect barrier function. Studies have shown that the acyl chain length of natural ceramides is usually 18-C, and the osmotic function of artificially prepared 4-C to 8-C acyl chain ceramide analogs is 10.8 times that of the maximum effect of 6-C acyl chain analogs. Short-chain ceramide reduces skin barrier function. Skolova et al. also confirmed that short-chain ceramides (12-C) prepared with shorter acyl chains (2-C, 4-C and 6-C) are more prone to skin than natural ceramides (18-C). Destruction of the barrier function. Therefore, the long chain of ceramide is necessary to maintain the normal function of the skin barrier. The amount of ceramide in the stratum corneum decreases with age. A decrease in ceramide can cause abnormal skin function, such as ceramide in dry skin lesions of patients with pruritic skin disease, which is significantly lower than normal skin.
1.2 Cholesterol is the main steroid substance in the stratum corneum
Compared with other tissues, the stratum corneum of the skin is rich in cholesterol sulfate, which plays an important role in regulating the polymerization and exfoliation of stratum corneum cells. Cholesterol sulfate is a substrate for steroid sulfatase enzymes that can cause ichthyosis with recessive inheritance of the X chromosome when the steroid sulfatase gene is mutated.
1.3 Free fatty acid stratum corneum
The free fatty acid stratum corneum is mainly composed of a linear free fatty acid of more than 20-C, and is the same as cholesterol sulfate, both of which are charged ionic groups, and thus it is considered to be involved in the formation of a lipid bimolecular membrane structure. At the same time, the secretion of free fatty acids is related to the pH value of the epidermis. The free fatty acids in the ionic state are responsible for the change of pH value, and the pH value is maintained between 4.0 and 5.5. The pH of the stratum corneum can control the physical properties and stability of the lipid membrane by adjusting the lateral structure of the membrane. Deprotonated free fatty acids affect the interaction between lipids and lipids, such as the tension of the lipid domain, such that the linkage between the lipid domains may be defective, that is, the membrane barrier is destroyed, thereby causing active infiltration.
2 Intercellular lipids and diseases
2.1 Psoriasis
Psoriasis in long-chain ceramides that bind free fatty acids in lesions of psoriasis and ceramide and sphingomyelinase levels containing 4-hydroxydihydrosphingosine are lower than their normal skin, but the total amount of ceramide No change indicates that the effect of ceramide reduction on the skin barrier may not be due to a decrease in total amount but to a disordered proportion of ceramide species.
2.2 Atopic dermatitis
The ceramides in skin lesions and non-lesional skin of patients with atopic dermatitis decreased, especially ceramide-1 decreased most. And for both, the composition of ceramides is also different. For example, the ceramide containing α-hydroxy fatty acid in the patient’s skin lesions is reduced, while the ceramide containing sphingosine is increased, and the normal skin is the opposite.
3 The structure of lamellar bodies and its effect on intercellular lipids
3.1 Structural lamellar body
The structural lamellar body is located in the epidermis and is oval in shape. It is a bilayer membrane secretory organelle with a size of about 0.2μm×0.3μm. It is formed by differentiation of keratinocytes. It is first seen in the upper part of the spinous layer and gradually moves up to the granular layer. And significantly increased. The lamellar body is a very complex secretory structure containing a variety of lipids, enzymes and proteins.
3.2 Effect on intercellular lipids
The lamellar bodies play an important role in the transport of lipids from the granular layer to the stratum corneum. Studies have shown that ABCA is a lipid transporter, and ABCA12 has an indispensable effect on the aggregation of glucosylceramide in lamellar bodies. Mutations in the loss of function of ABCA12 result in lamellar bodies not being able to synthesize normal substances and forming extracellular bimolecular lipid membranes. In the study of harlequin-like ichthyosis, it was found that the loss of ABCA12 function leads to a barrier to lipid transport in the stratum corneum, which causes HI, and thus is considered to be a transporter involved in the transport of keratoses. Akiyama et al. believe that ABCA12 has a partial loss of function, which is related to the occurrence of type 2 lamellar ichthyosis. But at present, it is unclear how cholesterol and phospholipids are transported to lamellar bodies.
When mechanical damage such as tape sticking repeatedly, local solvent or repeated cleaning of the cleaning agent causes acute damage to the skin barrier, the lamellar body and the lipid react rapidly to restore the barrier function.
4.1 Lamellar bodies
When the skin barrier is acutely damaged, the granular layer cells rapidly secrete and form precursor lamellar bodies, resulting in a decrease in the number of lamellar bodies in a short period, inhibiting lipid transport, and achieving initial repair of the stratum corneum lipid membrane. The newly formed lamellar bodies then appear in the granular layer and act quickly until the permeability barrier function is restored. Studies have shown that in the first 15 to 30 minutes before the barrier destruction, the lipid bilayer membrane structure in the upper part of the stratum corneum is destroyed and a large number of fissures appear. The existing lamellar bodies in the upper part of the granular layer will rapidly secrete and transport the corresponding substances. These substances are filled in the form of folded sheets in the keratinocyte space, resulting in the consumption of a large number of lamellar bodies. After about 30 minutes, the newly formed lamellar bodies began to appear in the granular layer, and secreted a large amount of lipids, proteins and the like to participate in the repair of the barrier until their functions returned to normal.
4.2 Ceramide sphingolipid is the backbone of ceramide
When the acute skin barrier is destroyed, the synthesis of sphingolipids in the epidermis is increased, and the activity of serine palmitoyltransferase involved in the synthesis of sphingolipids is also increased. Glucosylceramide is the most important sphingolipid in lamellar bodies and is synthesized by ceramides under the action of glucosylceramide synthase. The activity of glucosylceramide synthetase is mainly expressed in the upper layer of the epidermis. Studies have shown that the destruction of the acute barrier, the activity of glucosylceramide synthase does not increase. However, the local application of P4, inhibition of the activity of glucosylceramide synthetase, the repair of the acutely destroyed skin barrier is slowed down. This indicates that glucosylceramide plays an important role in the skin permeability barrier. In animal experiments by Jennemann et al., mice lacking glucosylceramide synthetase died shortly after birth. These mice showed abnormalities in lamellar bodies and stratum corneum structure, indicating that glucosylceramide synthase deficiency is small. The mouse has a defect in the skin barrier function.
4.3 Cholesterol
Cholesterol increases cholesterol production during the destruction of the acute skin barrier; the activity of β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase increases at both protein and RNA levels in the cholesterol-producing pathway. The expression of farnesyl pyrophosphate synthase and squalene synthase is also increased. HMC-CoA reductase activity began to increase at 15 min after acute barrier destruction, reached a maximum at 2.5 h, and became normal after 15 h. In animal experiments, mice lacking 3β-dehydrocholesterol reductase-Δ24 (3β-hydroxysterol-Δ24, an enzyme that catalyzes the conversion of dehydrocholesterol to cholesterol) showed a large amount of dehydrocholesterol in the epidermis. These mice die shortly after birth due to abnormal skin barriers, and this model is more indicative of the importance of cholesterol to the skin barrier. Abnormalities in the terminal pathways of other cholesterol production are also associated with skin abnormalities, further indicating the important role of cholesterol synthesis in the skin barrier. ABCA1 is a membrane transporter involved in the regulation of intracellular cholesterol levels. Increased expression of ABCA1, increased intracellular cholesterol levels; decreased ABCA1 expression and decreased intracellular cholesterol. When the skin barrier is acutely disrupted, ABCA1 expression is decreased, resulting in a decrease in intracellular cholesterol levels, and more cholesterol spillover is used for the recovery of the permeability barrier.
4.4 Fatty acid production increases when fatty acid skin barrier is acutely disrupted
The fatty acids in the stratum corneum are mainly characterized by a long-chain structure that affects the activation and/or expression of the enzyme when the skin barrier is destroyed. Studies have shown that animals lacking ELOVL4 have severe abnormalities in the skin barrier function and die shortly after birth. Lowering the level of ELOVL4 results in a shorter length of the N-acyl chain, which causes the lack of long-chain fatty acids in the ceramide, which leads to abnormal skin barrier and a decrease in the stratum corneum lipid membrane. Therefore, long-chain fatty acids play an important role in maintaining the normal barrier function of the skin.
The topical lipid mixture is mainly divided into two types, one is non-physiological lipids, such as mineral oil, petrolatum, lanolin, beeswax and the like. They do not enter the lamellar bodies to participate in their metabolic pathways, but can be filled between the stratum corneum cells to form a water-impermeable membrane that prevents the loss of water and electrolytes. These lipids can quickly repair part of the skin barrier function, but because the skin abnormalities are not fundamentally corrected, the skin barrier function cannot be completely restored to normal levels. The second type is physiological lipids such as ceramide, cholesterol, free fatty acids and the like. These lipids can enter the granulosa cells through the stratum corneum and can participate in the repair of the skin barrier by combining the lipids produced by themselves. Therefore, it is very important to prepare a physiological lipid mixture according to an accurate ratio. Otherwise, once the proportion is wrong, the structure of the lamellar body and the function of the skin barrier will be adversely affected. In different skin physiological and pathological conditions, the lack of lipids should be emphasized. For example, in aged and naturally aging skin, cholesterol production is significantly reduced. The use of cholesterol or cholesterol-based lipid products during treatment can achieve good results, while the use of fatty acid-based lipid products can hinder the skin. Repair of the barrier. The skin of patients with atopic dermatitis is mainly deficient in ceramide, so supplementation with ceramide or ceramide-based products is better than cholesterol-based. Studies have shown that short-term use of ceramide-based physiological lipid barrier repair agents is more protective than cholesterol when repairing skin with physical damage such as tape. In some cases, non-physiological and physiological lipids can also be used in combination to repair the skin barrier, because physiological lipids need to enter the cells to participate in metabolism before they can produce a repair barrier, resulting in a certain time delay, such as joint use. Non-physiological lipids can form a non-permeable membrane in time to prevent further loss of water and electrolytes.
In summary, epidermal cell lipids and lamellar bodies play a crucial role in maintaining skin permeability barrier function through a series of complex and precise biochemical reactions. Clinically, the use of exogenous lipid mixtures is reliable and effective in the treatment of skin barrier dysfunction due to a decrease in intercellular lipids. Therefore, for patients with different lipid components, it is necessary to develop and apply a more targeted lipid external preparation.
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