Background: Linoleate-containing acylglucosylceramide (GLC-CER[EOx], where x = sphingosine [S], dihydrosphingosine [dS], phytosphingosine (P), or 6-hydroxysphingosine [H]) in the viable epidermis serve as the precursors to the linoleate-containing acylceramides (CER[EOx]) in the stratum corneum (SC) and the corneocyte lipid envelope (CLE), both of which are essential for the barrier function of the skin. Summary: CLE formation and envelope maturation take place across the SC. Hypoxic conditions in the epidermis and anaerobic glycolysis with the production of lactic acid are important in proper SC barrier formation. Key Message: CLE formation takes place across the SC. Its formation from linoleate-containing GLC-CER[EOx] requires lipoxygenase action, but anaerobic conditions leading to lactate production and hypoxia-inducible factors are essential for proper barrier formation. A number of unanswered questions are raised regarding formation of the CLE and the epidermal permeability barrier.

Essential fatty acid deficiency was first described in 1929 by Burr and Burr [1], and in 1930, linoleic acid was identified as the fatty acid required to support normal growth and a healthy skin [2]. Rigorous exclusion of fat from the diet resulted in scaly skin, poor growth, and eventual death from kidney failure. Essential fatty acid-deficient rats could be cured by small amounts of oil or lecithin-containing linoleic acid. The deficient animals consumed more water than controls. This is now understood to reflect compensation for increased transepidermal water loss (TEWL) due to the poor permeability barrier function [3]. It was suggested in 1987 that lipoxygenase action may be involved in formation of the epidermal permeability barrier [4]. This expectation is now an accepted fact [5]. The action of two lipoxygenases is required to generate CER[Ox] species that become attached to the outer surface of the corneocyte lipid envelope (CLE) as shown in Figure 1.

Fig. 1.

Metabolic pathway leading from GLC-CER[EOS] to CER[EOS] and the CLE consisting of CER[OS] ester-linked to the outer surface of the cornified envelope.

Fig. 1.

Metabolic pathway leading from GLC-CER[EOS] to CER[EOS] and the CLE consisting of CER[OS] ester-linked to the outer surface of the cornified envelope.

Close modal

In 1932, linolenic acid was identified as an essential fatty acid [6], but understanding the significance of the ω-3 fatty acids for human health was slow to develop [7]. Meanwhile, it was shown that linoleic acid served as a precursor for arachidonic acid [8]. The metabolism of arachidonic acid to produce prostaglandins and other eicosanoids has been a major research area [9, 10]. It is now known that the scaly skin of essential fatty acid-deficient rats described by Burr and Burr reflects epidermal hyperproliferation and can be reversed by the topical application of prostaglandin E2 [11].

The linoleate-containing acylglucosylceramide (GLC-CER[EOx]) and the related acylceramide (CER[EOx]), and the possible derivatives thereof, are thought to account for the essential role of linoleic acids in the skin [3, 12‒15]. The linoleate-containing acylceramide is required for formation of the 13 nm long periodicity phase, which is required for proper barrier function [16, 17]. The GLC-CER[EOx] serves as the precursor of the CLE, which is thought to be necessary for proper barrier formation [18]. The purpose of this review is to summarize our current state of knowledge regarding these sphingolipids, the CLE, and the intracorneocyte environment.

The pioneering work of Gray and coworkers on epidermal lipids established that the epidermal lipids of pig and human epidermis are very similar, and much of the early work on the lipids of epidermis and stratum corneum (SC) focused on the porcine model [19‒22]. This was largely because porcine skin could be easily obtained in large quantities.

The linoleate-containing sphingolipids of the epidermis have received much attention for their essential roles in formation and function of the epidermal permeability barrier; however, review of this literature reveals little published information on the GLC-CER[EOx] and wide variation in the linoleate content reported for the CER[EOx].

The first such detailed structural analysis was published in 1978 [22]. Although some major aspects of the proposed structure were incorrect, this lipid ultimately proved to be GLC-CER[EOS]. Linoleate was found to represent 77.4% of the ester-linked fatty acids in the lipid isolated from pig epidermis and 56.4% in the same lipid isolated from human epidermis. Another published report of the ester-linked fatty acids from human GLC-CER[EOS] reported 58.4% linoleate [23].

In accordance with these findings, it was found that 74.5% of the ester-linked fatty acid in CER[EOS] from pig epidermis consisted of linoleate [12], and 70.0% linoleate was found in the GLC-CER[EOS] [13]. The major ester-linked fatty acids other than linoleate ranged from 14-20 carbons with the major entities being C16:0, C18:0, C16:1, and C18:1. It was also established that the ester-linked fatty acids were attached to the ω-hydroxyl group of the ω-hydroxyacid [13]. Subsequent studies confirmed this structural feature and demonstrated that the ester-linked fatty acids in GLC-CER[EOS] were also attached to the ω-hydroxyl group [14]. This study also demonstrated that 90% of the sugar in GLC-CER[EOS] is glucose and 10% is galactose.

These studies established the amide-linked fatty acids in GLC-CER[EOS] and CER[EOS] to be long-chain ω-hydroxyacids ranging from 20-34 carbons in length [12, 13]. The major entities were 30:0, 32:1, and 34:2. The relative proportions of saturated, monounsaturated, and dienoic ω-hydroxyacids were 57% saturated, 35.5% monounsaturated, and 7.5% dienoic.

In 1989, a report described GLC-CER[EOS] and GLC-CER[EOP] from human epidermis [24]. These two ceramides were said to be present in about equal amounts, and the ester-linked fatty acids in each were reported to be greater than 95% linoleic acid. There is a reason to believe that what was reported as GLC-CER[EOP] was a mixture of GLC-CER[EOP] and GLC-CER[EOH]. The sphingoid base in what was reported to be GLC-CER[EOP] was identified as a trihydroxy sphingoid base, and phytosphingosine was the only trihydroxysphingoid base known to be found in epidermal sphingolipids at the time.

When covalently bound lipids in the human SC were first examined, two species were found [25]. These were ceramide A (CER[OS]) and ceramide B, a species consisting of an ω-hydroxyacid amide linked to a trihydroxy base, which was subsequently identified as 6-hydroxysphingosine [26]. A minor component of the ceramide B fraction was later identified as CER[OP] [27]. Since the covalently bound ω-hydroxyceramides are ultimately derived from the analogous GLC-CER[EOx], it would seem likely that what was reported as a phytosphingosine-containing GLC-CER[EOx] actually contained both 6-hydroxysphingosine and phytosphingosine. This argument was strongly supported by NMR data later reported for human CER[EOH] [28]. This same report included the ester-linked fatty acid compositions for CER[EOS], CER[EOH], and CER[EOP] [28]. The weight percentages of ester-linked linoleate in CER[EOS], CER[EOH], and CER[EOP] were 72.4, 19.5, and 8.2, respectively. All three contained 16 through 26-carbon saturated fatty acids, and CER[EOS] and CER[EOH] contained octacosanoic acid. Only CER[EOS] contained oleic acid (8%), and CER[EOP] contained notably higher proportions of palmitic (25%) and stearic acids (15%) and no octacosanoic acid.

All of the analyses of the ester-linked fatty acids in these studies were done by gas-liquid chromatography of fatty acid methyl esters. Methyl esters were generally prepared by standard acid methanolysis [15, 22] or boron trichloride in methanol [12, 13, 28]. The study by Hamanaka et al. [24] used treatment of fatty acids with diazomethane in ethyl ether to convert fatty acids to methyl esters [29]. This is a general method converting carboxylic acids to methyl esters or phenols to phenolic ethers. However, the reaction of fatty acids with diazomethane in ethyl ether is slow and can be incomplete. This can be overcome by the inclusion of a small percentage of methanol in the ethyl ether [30]. The NMR spectra presented support to the high proportion of ester-linked linoleate in the reported GLC-CER[EOx].

For the porcine lipids, there were three studies in which the ester-linked fatty acid composition was determined for both GLC-CER[EOS] and CER[EOS] from the same sample. In each of these studies, the percentage of linoleate was high and nearly equal for the two sphingolipids. In one study, the linoleate contents of GLC-CER[EOS] and CER[EOS] were 74.0 and 74.5%, respectively [12, 13]. In a second study, the percentages of linoleate were 66.0% for GLC-CER[EOS] and 70.0% for CER[EOS] [15]. In young pigs, both GLC-CER[EOS] and CER[EOS] contained 55% linoleic acid among the ester-linked fatty acids [31]. This is notably lower than the linoleate content of these lipids found in more mature pigs. This is thought to be an age-dependent difference and will be discussed later.

The GLC-CER[EOS] is synthesized in and is localized to the viable epidermis, whereas the CER[EOS] is found in the SC. This is consistent with the view that the glucosylceramides are converted to ceramides by deglycosylation and the transfer of linoleate from GLC-CER[EOS] to CER[EOS] in pig epidermis [32, 33]. The percentage of linoleate found in human CER[EOx] and the collection methods are summarized in Table 1.

Table 1.

Linoleic acid content reported for human CER[EOS]

% C18:2ω6REFComments

41.3

 

[34]

 

250 mL of 95% ethanol slowly poured over forearms

 

12.0

 

[35]

 

400 mL of 95% ethanol poured over the scalp, aged 6–23-year old subjects

 

22.2

 

[36]

 

500 mL of 95% ethanol slowly poured over lower leg

 

29.7

 

[37]

 

250 mL of 95% ethanol poured over forearms

 

26.0

 

[38, 39]

 

2 × 3 cm cellotape strip × 8, summer value, winter 21%

 

20.0

 

[40]

 

Chloroform:methanol extraction of epidermal cyst contents

 

65.0

 

[28]

 

Chloroform:methanol extraction of the stratum corneum

 
% C18:2ω6REFComments

41.3

 

[34]

 

250 mL of 95% ethanol slowly poured over forearms

 

12.0

 

[35]

 

400 mL of 95% ethanol poured over the scalp, aged 6–23-year old subjects

 

22.2

 

[36]

 

500 mL of 95% ethanol slowly poured over lower leg

 

29.7

 

[37]

 

250 mL of 95% ethanol poured over forearms

 

26.0

 

[38, 39]

 

2 × 3 cm cellotape strip × 8, summer value, winter 21%

 

20.0

 

[40]

 

Chloroform:methanol extraction of epidermal cyst contents

 

65.0

 

[28]

 

Chloroform:methanol extraction of the stratum corneum

 

Table 1 lists the percentage of linoleate in human CER[EOS] collected by surface extraction with ethanol, tape stripping, or chloroform:methanol extraction of isolated cyst contents or SC. The reference number for each measurement is given. The tape stripping removed five layers of SC cells as revealed by electron microscopic examination [39]. The collection of lipid from the scalp was probably the least efficient collection method as much of the ethanol would have been prevented from reaching the skin surface by the presence of hair. This method was developed primarily for the collection of sebaceous lipids [41]. Some of the variations in linoleate content may have been seasonal [38, 39]. The ongoing consumption of linoleate-containing hydroxyceramide with envelope maturation also explains why the CER[EOS] from human epidermal cyst contents contained 20% linoleate among the ester-linked fatty acids [42‒44]. All of the sampling methods found much lower linoleate content compared to what was found in CER[EOS] extracted from the isolated SC using chloroform:methanol mixtures. The long-chain bases in CER[EOS] contained a small proportion of dihydrosphingosine. In the last listed study [28], the linoleate contents of CER[EOH] and CER[EOP] were 78 and 38%, respectively.

GLC-CER[EOS] and CER[EOS] have also been demonstrated in laboratory rodent epidermis [45‒49]. The GLC-CER[EOS] and CER[EOS] from mouse epidermis were similar to those of pig with 70.9 and 70.0% linoleate, respectively [45]. These lipids in the rat contained 32.0 to 53.3% linoleate [3, 46]. The analogous lipids from guinea pig epidermis were rich in ester-linked linoleate, but detailed compositions were not reported [47‒49].

CER[EOS], CER[EOdS], CER[EOP], and CER[EOH] have been demonstrated in the SC from dogs [50‒55]. In general, the ceramide profile of dog SC was more complex than those of pigs or rodents. It was closer to what has been found in humans. These analyses were mostly done by thin-layer chromatography, and no details of the ester-linked fatty acids in CER[EOx] were reported.

Studies of isolated CLEs have revealed two morphologically distinct populations, irregularly shaped and fragile, designated CEf and polygonal and rigid, designated CEr [56]. Examination of CLEs from tape stripping of the normal human SC revealed that CEf predominated in the inner SC, while CEr were more abundant in the outer layers of the SC.

This maturation process involves both increased cross-linking of protein via transglutaminase 1 (TGM1) and increased attachment of ω-hydroxyceramide to the outer surface of the CLE, leading to increased hydrophobicity [57, 58]. The maturation of the CLEs is also accompanied by a redistribution of corneodesmosomes from a random pattern to a honeycomb pattern, in which the corneodesmosomes are located along the boundaries of adjacent cells [56]. This maturation process largely determines the biomechanical properties of the individual cells and may be of significance for flexibility of the skin and for the desquamation process.

Why are the linoleate contents of CER[EOS] collected by ethanol rinsing, tape stripping, and from epidermal cyst contents so much lower than that found in CER[EOS] from the extracted SC? These methods sampled only the superficial SC, and it is suggested that the consumption of linoleate-containing CER[EOS] in the maturation of CLEs has depleted linoleate-containing CER[EOS] by the time cells reach the outer SC. Consistent with this view, the contents of the epidermal cyst, which were thoroughly extracted with chloroform:methanol, are exfoliated corneocytes.

Isolated lamellar granules have been found to be enriched in GLC-CER[EOx] [59‒61]. It has been suggested that much of this GLC-CER[EOx] is in the bounding membrane of the lamellar granule, and is positioned to be converted into covalently bound ω-hydroxyceramide on the outer surface of the nascent CLE when the bounding membrane of the lamellar granule fuses into the plasma membrane of the granular cell [18, 62]. Presumably, after the removal of glucose by β-glucocerebrosidase, this CER[EOx] itself could provide a template upon which the intercellular lipid lamellae could spread out.

There are several mechanisms by which the ω-hydroxyceramide could become covalently linked to the CLE. One of these is based on a demonstration that a synthetic analog of a long-chain ω-hydroxyceramide became ester-linked to a CLE protein, involucrin, through the action of TGM1 [63]. This would require an as-of-yet unidentified esterase to remove the ester-linked fatty acid from CER[EOx]. This mechanism has not been demonstrated in skin, but may be of significance for the CER[EOx] containing esterified fatty acids other than linoleate. Two other methods have been demonstrated for the linoleate-containing CER[EOx]. Both of these require sequential oxidative attacks on the linoleate by 12R-LOX followed by eLOX3 resulting in formation of a 9,10-epoxy-13-hydroxy-11E-octadecenoic acid. The epoxide can be acted upon by an epoxide hydrolase to give a trihydroxy derivative of linoleate, 9,10,13-trihydroxy-11E-octadecenoic acid, which can be removed by an esterase. The resulting ω-hydroxyceramide can then be attached to the CLE by TGM1 [64]. Alternatively, the 13-hydroxyl group can be oxidized to a ketone, which can spontaneously bind to the surface of the CLE through Shiff base formation with amino groups [65]. Using tape stripping, gradients of the multiple oxidized intermediates in conversion of linoleate-containing CER[EOx] to covalently bound CER[Ox] and the 9,10,13-trioxilin in the outer SC have been demonstrated [59, 66]. In healthy human SC, the inner layers of the SC contained more 9,10-epoxy, 13-hydroxy-CER[EOS], while the outer layers contained more 9,10,13-trihydroxy-CER[EOS] [59]. 9,10,13-trihydroxy-11E-octadecenoic acid is presumed to be cleaved from the CER[EOx] prior to attachment of the ω-hydroxyceramide to the CLE [64]. It has been suggested that the 9,10,13-trihydroxy-11E-octadecenoic acid may serve as a signaling molecule in barrier homeostasis [64].

Linoleic acid is required in the neonatal mammalian diet for proper growth and maturation and maintenance of the permeability barrier of the skin [2, 3]. The diet of commercially raised pigs is generally rich in linoleic acid because it contains corn as a major component [67]. Largely due to the widespread use of lineolate-rich vegetable oil, the human diet generally has an ample supply of linoleate [68]. Essential fatty acid deficiency in humans is rarely seen in the absence of general malnutrition. However, a high ratio of ω-6 to ω-3 fatty acids in the diet can lead to cardiovascular diseases or other inflammatory disorders [68]. During fetal development, the source of essential fatty acids is the maternal circulating fatty acid pool as transferred through the placenta. The placenta actively selects for transfer of arachidonic acid and eicosahexaenoic acid, which are required for development of the neurological and immune systems [69, 70]. The transfer of linoleic acid is relatively low. As a result, full-term infants have higher TEWL than adults [71‒75]. It takes five to six years before TEWL drops to match adult levels [74, 75]. Preterm infants have even poorer barrier function and require special care to avoid dehydration [76, 77].

In an experiment with mice, the linoleate content of GLC-CER[EOx] was examined as a function of age [78]. The linoleate content of the GLC-CER[EOx] in the newborn mouse was 12%. This rose to 30% within 1 week and plateaued at 45% at about 45 days. Given that the maximum life expectancy of a C57BL laboratory mouse is 30 months, this takes the first 5% of the mouse’s life to attain the adult level of linoleate in the GLC-CER[EOx]. In the absence of disease and accidental death, the maximum human life span is about 120 years. The 5–6 years required for maturation of the permeability barrier as judged by TEWL represents the first 4–5% of the human life. The pigs, noted above, whose CER[EOx] and GLC-CER[EOx] contents were about 55%, were fed on a diet containing lard as a source of linoleic acid. They were 5 days old when obtained from a farm, and were fed linoleate-containing diet for less than 1% of their maximum life expectancy. This may explain why the linoleate content of these sphingolipids was less than the 74–75% seen in more mature animals.

The epidermis is avascular. Nutrients and oxygen diffuse from the capillary beds in the papillary dermis to the epidermis, and oxygen also diffuses through the SC [79]. In the lower layers of the epidermis, energy production reflects a combination of glycolysis, Krebs cycle activity, and β-oxidation of fatty acids [80]; however, within the granular layer, the mitochondria are degraded and energy production is achieved exclusively by anaerobic glycolysis with the production of lactic acid [81, 82]. This transition in energy production may be due to the mild hypoxic condition within the viable epidermis [83]. Anaerobic glycolysis is commonly seen in solid tumors and in muscle tissues during vigorous exercise. In epidermis, lactate is a significant part of natural moisturizing factor [84]. It is also one of several contributors to the low pH at the boundary between the upper granular layer and the bottom of the SC, which is necessary for the enzymatic conversion of sphingomyelin and glucosylceramides into ceramides [29, 85]. The lowered pH and the increase in free Ca++ that occurs as the internal membranous organelles are degraded, both increasing the activity of 12R-LOX and eLOX3 [86, 87]. In addition to providing lactic acid, the shift to anaerobic glycolysis provides adequate ATP production while sparing oxygen for other enzymatic processes, such as 12R-LOX and eLOX3, which are necessary for formation of the CLE. The mild hypoxic environment in the viable epidermis favors the expression of hypoxia-inducible factors (HIFs) [88]. HIF1α and HIF2α have been shown to regulate both expression of the filaggrin gene (flg) and formation of the permeability barrier [89]. The levels of HIF are low under normal oxygen conditions due to binding to von Hippel-Lindau protein and post-translational modifications leading to proteolytic degradation. Nitric oxide (NO) synthase is expressed in epidermal keratinocytes [90]. Under hypoxic conditions, NO and reactive oxygen species produced endogenously stabilized HIF [91]. NO produced endogenously can react with a variety of unsaturated fatty acids to produce nitro-fatty acids [92]. Nitro-fatty acids can both upregulate and activate PPAR-γ [93‒95]. Activation of PPARγ has been shown to increase the rate of synthesis of fatty acids, cholesterol, and ceramides in epidermis [96]. These lipids, along with the CLE, constitute the epidermal permeability barrier.

Atopic dermatitis and psoriasis are relatively common inflammatory skin diseases in which the permeability barrier function is compromised as judged by increased TEWL [97, 98]. It has long been known that the ceramide content of the SC is reduced in atopic dermatitis, although this depends upon disease activity [99‒101]. In general, there was little difference between the SC lipid composition between control subjects and atopic subjects when there were no active lesions on the atopic skin; however, when there was disease activity, the ceramide content of the SC in the uninvolved atopic skin was reduced. In several of the early studies, CER[EOS] was among the most affected ceramides [99‒101]. In a more recent analysis, total ceramides were somewhat reduced in the SC of uninvolved atopic skin and the reduction was greater in lesional areas [102]. CER[EOdS], CER[EOS], CER[EOP], and CER[EOH] were quantified. There appears to be a small reduction among these ceramide fractions between the control and nonlesional atopic skin and a larger reduction between control and lesional regions. The CER[AS] and CER[NS] fractions were increased in the atopic SC, particularly at the lesional sites. This was related to the expression of β-glucocerebrosidase and acid sphingomyelinase. Another study indicated that covalently bound ω-hydroxyceramides were decreased in atopic dermatitis [103]. However, the proportion of covalently bound ω-hydroxyacids went up. It is possible that ceramidase action to release long-chain base took place leaving behind the ω-hydroxyacid. This study also noted that the free fatty acids in the atopic SC were of shorter chain lengths than normal. A second recent study employing HPLC-MS did not find a reduction of covalently bound ω-hydroxyceramides in atopic dermatitis [104]. It was found that the covalently bound ceramides had a higher proportion of monounsaturated ceramides, and the sphingosine-containing subclass of covalently bound ceramides was increased. The covalently bound ceramides had shorter chains. The differences in the covalently bound ceramides were reflected in the free ceramide precursors.

There was an early report of a reduced proportion of CER[EOS] in a psoriatic scale [105]. It has more recently been demonstrated that the total lipid content of the psoriatic SC is not significantly different from that of the normal SC, but the ceramide composition is altered [106]. Specifically, phytosphingosine-containing ceramides were decreased while sphingosine-containing and dihydrosphingosine-containing ceramides increased. There were small proportions of CER[EOdS] in both normal and psoriatic SC that did not differ. The proportions of CER[EOS], CER[EOP], and CER[EOH] were each lower in the psoriatic SC. The total fatty acid content was reduced significantly in the psoriatic SC, and the proportion of moneoic fatty acids was increased. Cholesterol sulfate was significantly elevated in the psoriatic SC. The cholesterol level was not determined. The presence of 9,10,13-trihydroxy-11E-octadecenoic acid in the superficial layer of the SC provides evidence that there was some GLC-CER[EOx] available for formation of a CLE [66], but the levels of oxidized CER[EOx] were generally lower than normal across the SC suggesting that formation of the CLE was not complete [66].

The enzymes of the biosynthetic pathway leading to the synthesis of linoleate-containing CER[EOx] and the CLE have largely been identified because mutations in the genes coding for these enzymes result in autosomal recessive congenital ichthyoses. The enzymes involved include fatty acid elongases 1 and 4, ceramide synthase 3, fatty acid transport protein 4, patatin-like phospholipase domain-containing 1, α/β-hydrolase domain-containing 5, and the lipoxygenases 12R-LOX and eLOX3. This has been reviewed [18, 61, 107, 108]. Mutations in gene coding for TGM1 result in lamellar ichthyosis [109].

It is well established that GLC-CER[EOx] serves as the precursors for CER[EOx] in the intercellular spaces of the SC and covalently bound CER[Ox] of the CLE; however, there are a number of outstanding questions regarding the details of these transformations:

  • 1.

    When is the glucose actually removed in formation of the CLE? Most published synthetic schemes indicate that this occurs after attachment of the ω-hydroxyceramide to the CLE. This appears to be largely based on the finding that in a β-glucocerebroside deficient mouse, GLC-CER[EOx] becomes covalently attached to the CLE [110]. There is a small amount of covalently attached CER[OS], which may be derived from the small amount of GLC-CER[EOx] that contains galactose instead of glucose. Since attachment of ω-hydroxyceramides appears to occur across the SC with most attachment in the outer layers, one might expect to find GLC-CER[EOx] among the extractable SC lipids. This is not the case [111].

  • 2.

    How do CER[Ox] derived from approximately 30% of GLC-CER[EOx] that do not contain linoleate become attached to the CLE? What lipase could hydrolyze the ester-linked fatty acid? Is this the same as the unknown esterase that liberates the trihydroxy fatty acid derived from linoleate? Three new lipase genes that are expressed in keratinocytes from the granular layer have been identified [112].

  • 3.

    What is the significance of the monoenoic and denoic ω-hydroxyacids in the GLC-CER[EOx] and CER[EOx]? Unsaturation of these ω-hydroxyacids increases in essential fatty acid deficiency [46]. Does this influence lateral chain packing?

  • 4.

    Does 9,10,13-trihydroxy-11E-octadecanoic acid play a regulatory role in barrier homeostasis?

  • 5.

    What are the relative roles of transglutaminase-mediated versus Schiff base attachment of ω-hydroxyceramides.

I look forward to learning the answers to these questions as well as unanticipated surprises.

The author wishes to thank Nancy Wertz for assistance in preparation of this manuscript.

The author has no conflict of interest to declare.

There was no funding to support this work.

Philip W. Wertz researched and wrote this review article.

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