Structure and Physicochemical Characteristics of Ceramides
CERs are predominant lipid components of the
stratum corneum and comprise 30–40% of the
stratum corneum lipids by mass. They are composed of long-chain sphingoid bases (
dihydrosphingosine, sphingosine, phytosphingosine or 6-hydroxysphingosine) which are linked to long chain free fatty acids (
non-hydroxy fatty acids, α-hydroxy fatty acids or ester-linked ω-hydroxy fatty acids)
via amide bonds (
Figure 3). Hence, the head groups in CERs include hydroxyl groups that can form inter- and intramolecular hydrogen bonds. The number of hydroxyl groups in the head group of CERs is important for integrity of the
stratum corneum’s barrier function. Also, CERs exhibit the heterogeneity in terms of chain length (16–30 carbons) and degree of unsaturation (predominantly saturated) and hydroxylation pattern. The chain length of fatty acids in the CERs generally is 24–26 carbons, but there are slightly available fatty acids comprising 16–18 carbons [
22], and their chain length affects the skin permeability and barrier function of the
stratum corneum [
23].
Considering the chemical structure of CERs, they are highly lipophilic compounds because the ratio of long-chain fatty acids to the hydrophilic head part is high. As such, CERs are poorly water-soluble compounds [
24]. Also, CERs are compounds with high molecular weight [
25]. Because of the aforementioned physicochemical characteristics of CERs, the percutaneous absorption of these compounds is limited when topically applied to the skin. Besides this issue, CERs exhibit polymorphic characteristics which resulted in some questions during the fabrication of ceramide formulations [
26].
There are an available 12 types of extracted CERs in the human
stratum corneum, which are derived from the aforementioned types of fatty acids and sphingoid bases, differing from one another based on the composition of the head group or esterification of fatty acids (
Figure 4) [
27,
28].
Biosynthesis of Ceramides in the Skin
The production of CERs could be from different metabolic pathways. These are the de novo biosynthesis pathway, SMase pathway (activation of sphingomyelinases) and salvage pathway [
29]. In the de novo pathway, ceramide biosynthesis occurs in the endoplasmic reticulum of corneocytes in the
stratum basale. For the synthesis of CERs, L-serine amino acid and palmitoyl CoA are primarily condensed
via serine palmitoyl transferase. The first long-chains of CERs form and these molecules are named as 3-ketodihydrosphingosine. 3-ketodihydrosphingosine undergoes a reduction reaction for conversion to dihydrosphingosine. Then, dihydrosphingosine is converted to dihydroceramide by acylation. Finally, dihydroceramide is catalyzed by dihydroceramide desaturase to synthesize CERs [
30,
31]. The salvage pathway occurs in the acidic subcellular compartments, such as the late endosomes and the lysosomes. In these compartments, sphingosine-1-phosphate is converted to sphingosine
via sphingosine kinase. Then, sphingosine is converted to CERs by ceramide synthase. SMase pathway occurs in the plasma membrane and the endosomal/lysosomal compartments. CERs are formed by hydrolysis of sphingomyelin by SMase [
29,
31].
On the other hand, salvage and SMase pathways are reversible metabolic processes, therefore they behavelike a control mechanism to keep constant the ceramide, fatty acid and cholesterol ratio. In this way, CERs are taken under the control and reach the upper layer of the skin even through the
stratum corneum. They harmonize to corneocyte about forming the "brick-mortar" model and organization occurs regularly thanks to their head-tail structure [
29].
Location and Position of Ceramides in the Skin
The lateral and lamellar organization of lipids is crucial for the barrier function of the skin. The lateral organization is the arrangement of the lipids vertically to the plane of lamellar lipid organization. There are three possible organizations in intercellular spaces: (i) fluid organization, which is the most disordered and highly permeable, (ii) hexagonal organization, which is less dense and medium permeable, and (iii) orthorhombic organization, which is a highly ordered state and exhibits low permeability [
32,
33,
34]. In the orthorhombic organization, highly ordered state is based on Van der Waals interactions in the tails and hydrogen bonds in the head groups of the lipids [
35,
36] and the ceramide molecules are organized with width and length as 0.41 nm and 0.37 nm in per 0.182 nm
2 area, respectively [
37]. Besides, in the hexagonal organization, the ceramide molecules are arranged in an order having equal width and length as 0.41 nm in per 0.194 nm
2 area, respectively. Also, the width and length are angled as 120° in a hexagonal structure because of weakened interactions, as distinct from orthorhombic organization. These structural diversities make the hexagonal structure less constricted, probably causing changes in skin barrier function. Nevertheless, the hexagonal structure in regular order provides a sufficient barrier function rather than a fluid organization that the ceramide molecules could be disorganized in the skin [
38].
In the lamellar organization, the lipids which are ordered as bilayers are arranged with different periodicity phases. If the lipids repeat in per 6 nm interval, the alignment is identified as a short periodicity phase (SPP). On the other hand, it is named as a long periodicity phase (LPP) if the lipids recur in per 13 nm interval [
34,
38].
Role of Ceramides in the Skin Barrier and Skin Disorders
The morphology of ceramide holding the corneocytes and attaining to intercellular matrix knits the skin and remain the skin integrity. The ordered alignment of lipid forms a closed system to prevent TEWL and makes the stratum corneum more impermeable. As a result, changes in the amount and organization of the stratum corneum CERs cause skin disorders with barrier defects.
Atopic Dermatitis: Atopic dermatitis is a dermatological disorder which is characterized by dry skin, pruritus, increased TEWL, and decreased skin barrier function. Matsumoto et al. [
39] reported that the ceramide I, long-chain ceramide, decreased by 52% in atopic dermatitis. In addition, ceramide V in non-lesionedparts of the skin were raised, and ceramide I and ceramide III were reduced in lesioned parts of the skin [
40,
41]. Moreover, the metabolism pathways such as ceramidase are overactive in the epidermis with atopic dermatitis [
42]. Besides, Chermprapai et al. [
43] determined that free fatty acids were reduced as well as CERs in the atopic dermatitis.
Ichthyosis: As much as atopic dermatitis, free fatty acid ratio reduces in contradistinction for CERs ratio. Also, orthorhombic organization and LPP, having crucial roles in the skin barrier function, degenerate inichthyosis patients [
44]. In Dorfman-Chanarin syndrome, ichthyosis is also shown as a symptom with descending w-OH-acylceramide and w-O-acylceramide [
45]. Additionally, ceramide synthase 3 enzyme synthesizing the ceramide 3 has gene damage in a patient with congenital ichthyosis [
46].
Psoriasis: In another skin disorder in which barrier defects occurs, Motta et al. [
42] revealed the relation between ceramide composition and TEWL in psoriatic and healthy skin. According to results, ceramide I, III, IV, V, and VI reduced TEWL increased in all psoriatic scales.
Acne: It is considered that altered ceramide values is also effective on acne. Because of high-level TEWL in acne, altered ceramide could have a role in this point. Pappas et al. [
47] examined the correlation between them. However, TEWL is not negatively correlated with symptoms even though all subclasses of ceramide are negatively correlated with TEWL. Therefore, they considered the ceramide composition of healthy skin and skin with acne according to season. As a result, decreased ceramide aggravates the symptoms, especially in winter months. Seasonal changes in the amount of ceramide are exposed by increasing TEWL. On the other hand, healthy skin has high-level ceramide VI and VIII providing adaptation of environmental conditions in winter months.
Gaucher Disease: As a genetic disorder, Gaucher disease arising from β-glucocerebrosidase enzyme deficiency is also related to the ceramide biosynthesis and metabolism pathway. On glucosylceramide breaking down to glucose and ceramide, β-glucocerebrosidase has a role with hydrolyzation. After this stage, glucosylceramide is diminished and a ceramide molecule is exposed. However, in patients with Gaucher disease, this metabolism pathway loses the function because of β-glucocerebrosidase deficiency. Unlike the aforementioned disorders, a decrease in the amount of ceramide in Gaucher disease is originated from this point [
48].
Dry Skin: The lipid envelope, LPP, and orthorhombic organization keep the moisturizing balance under control and reduce TEWL. In this way, even though the skin is not moisturized by supplementary products, hydration content is preserved in skin layers. With decreasing ceramide levels in the skin, the barrier function of lipid envelopes becomes incapacitated. Compared to dry and normal skin, ceramide I, II, III, IV, V and VI diminish with dryness, while CERs are at a high level in normal skin [
39].