Topical Cholesterol Treatment of Recessive X-Linked Ichthyosis

Lykkesfeldt, G; Høyer, H

doi:10.1016/s0140-6736(83)91093-0

Cited by 40 publications

(21 citation statements)

References 7 publications

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“…Several published reports have addressed the alterations of physical properties of corneocyte lipids from excess CSO 4 (14 -16). It has been shown that CSO 4 can cause phase separation of cholesterol-fatty acid layers (14) and that the XI phenotype can be ameliorated by topical cholesterol treatment (17). Thus it was suggested that XI arises due to a defect of intercorneocyte lipid layer formation.…”

mentioning

confidence: 99%

Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

Nemes¹,

Demény²,

Marekov³

et al. 2000

Journal of Biological Chemistry

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The loss of transglutaminase 1 enzyme (TGase 1) activity causes lamellar ichthyosis. Recessive X-linked ichthyosis (XI) results from accumulation of excess cholesterol 3-sulfate (CSO 4 ) in the epidermis but the pathomechanism how elevated epidermal CSO 4 causes ichthyosis is largely unknown. Here we provide evidence that XI is also a consequence of TGase 1 dysfunction. TGase 1 is a key component of barrier formation in keratinocytes: it participates in the cross-linking of cell envelope (CE) structural proteins, and also forms the lipid bound envelope by esterification of long chain -hydroxyceramides onto CE proteins. Using involucrin and an epidermal -hydroxyceramide analog as substrates, kinetic analyses revealed that at membrane concentrations above 4 mol %, CSO 4 caused a marked and dose-dependent inhibitory effect on isopeptide and ester bond formation. Sequencing of tryptic peptides from TGase 1-reacted involucrin showed a large increase in deamidation of substrate glutamines. We hypothesize that supraphysiological levels of CSO 4 in keratinocyte membranes distort the structure of TGase 1 and facilitate the access of water into its active site causing hydrolysis of substrate glutamine residues. Our findings provide further evidence for the pivotal role of the TGase 1 enzyme in CE formation.Assembly of an effective epidermal barrier structure is an essential adaptation to terrestrial life. In mammals the outermost bulwark of this barrier is the cornified layer of the epidermis, composed of flattened corneocytes mortared together by orderly lipid laminae. During terminal differentiation, individual corneocytes acquire a specialized cell peripheral structure termed the cornified cell envelope (CE), 1 which is responsible for maintenance of mechanical and chemical protection and indirectly contributes to water permeability barrier (see Refs. 1 and 2, for reviews). The CE is composed of two parts. The ϳ10 nm thick protein envelope is formed by covalent cross-linking of several structural proteins by sulfhydryl oxidases and transglutaminases (TGases). This highly insoluble protein meshwork is coated by the lipid envelope, a ϳ5 nm thick layer of -hydroxyceramides with uniquely long (C 28 -C 36 ) fatty acyl moieties (3). These are covalently attached by ester bonds through their -hydroxyl group to selected glutamines to envoplakin, periplakin, and involucrin components of the protein envelope (4).Terminal differentiation of keratinocytes is accompanied by vigorous lipid metabolism and synthesis of keratinization-specific lipids in the granular layer. Newly synthesized lipids are temporarily stored in cytoplasmic lamellar bodies, in which they are arranged as stacks of tetralaminar sheets. The lamellar body lipids consist largely of free fatty acids, (glucosyl)ceramides, cholesterol, and its acyl or sulfate esters (3). In the uppermost granular layer the lamellar bodies fuse with the cell membrane, and release their contents which assume broad, multilamellar lipid sheets between corneocytes. This process approxima...

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confidence: 99%

Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

Nemes¹,

Demény²,

Marekov³

et al. 2000

Journal of Biological Chemistry

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“…Cholesterol sulfate and cholesterol in the SC are important factors regulating the desquamation of corneocytes, as cholesterol sulfate inhibits desquamation [24][25][26][27]32] and cholesterol cancels the inhibition by cholesterol sulfate [9,28,29,32] . In addition, the physical properties of membranes are altered by changes in the cholesterol:cholesterol sulfate ratio [39] .…”

Section: Discussionmentioning

confidence: 99%

“…Feingold et al [9] reported that lovastatin, an inhibitor of cholesterol synthesis, produced generalized defects in desquamation as well as in the barrier function. Several reports demonstrated that topical treatment with cholesterol is effective in improving desquamation in RXLI or RXLI model skin [28,29] . Therefore, cholesterol sulfate and cholesterol are important factors in the aged SC regulating the desquamation of corneocytes.…”

mentioning

confidence: 99%

Acceleration of de novo Cholesterol Synthesis in the Epidermis Influences Desquamation of the Stratum Corneum in Aged Mice

Haratake

Komiya

Horikoshi

et al. 2006

Skin Pharmacol Physiol

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Cholesterol, a component of intercellular lipids, is important for stratum corneum (SC) homeostasis, including its barrier function and desquamation. However, cholesterologenesis in the epidermis decreases under basal conditions with aging. We found that the number of horny layers in murine SC increased with the decrease of desquamation in the outermost corneocytes associated with aging. The cholesterol content decreased and the cholesterol sulfate content increased in the horny layer with aging, which resulted in an increase in the ratio of cholesterol sulfate to cholesterol. Moreover, we investigated the effects of accelerated cholesterologenesis on desquamation in aged murine skin following topical application of mevalonic acid. The ratio of cholesterol sulfate to cholesterol in aged murine SC significantly decreased following topical treatment with mevalonic acid, which resulted from an increase in cholesterol content via the acceleration of cholesterologenesis. Treatment with mevalonic acid also significantly reduced the number of cell layers in the SC along with the acceleration of desquamation, as measured by desmoglein I content, corneocyte surface area and proteinase activity. These results indicate that an improvement in the ratio of cholesterol sulfate to cholesterol content by de novo cholesterologenesis may be important for desquamation of the SC in aged epidermis.

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“…In addition, the ratio of cholesterol/CS is thought to be important in cohesion and desquamation; cholesterol is involved in desquamation and CS in cohe sion [1,9], In our results, the ratio of cholesterol/CS in the oral mucosa was 13.8 indicating that active turnover of the cells occurred in the epithelium, but the signifi cance of the ratio of cholesterol/CS in the pseudostratified epithelium (the nasal and tracheal mucosae) is un clear.…”

Section: Discussionmentioning

confidence: 99%

Significantly High Synthetic Activities of Cholesterol Sulfate in the Nasal, Oral and Tracheal Mucosae of Guinea Pigs

Higo

Iwamori²

1995

ORL

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Cholesterol sulfate (CS) is widely distributed in mammalian tissues and various physiological roles for it have been suggested, but the presence of CS in the nasal tissues has not yet been reported. This is the first report in which the CS content and the activity of its regulatory enzymes, cholesterol sulfotransferase (CST) and cholesterol sulfate sulfatase (CSS), in the nasal mucosa of the guinea pig were examined and compared with those in the oral and tracheal mucosae. The highest concentration of CS was detected in the oral mucosa and the second highest in the nasal mucosa. The activity of CST was also highest in the oral mucosa and the second highest in the nasal mucosa. On the other hand, that of CSS was highest in the tracheal mucosa. The accumulation of CS is assumed to be related to squamous differentiation, because the activity of transglutaminase type 1 in the nasal, oral and tracheal mucosae coincided with the order of the concentration of CS in those tissues. These results suggested that the accumulation of CS is correlated with the morphological differences between the oral stratified squamous and the nasal or tracheal pseudo-stratified epithelium, and furthermore that the nasal epithelium is more susceptible to squamous metaplasia than the tracheal epithelium in the guinea Pig.

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Topical Cholesterol Treatment of Recessive X-Linked Ichthyosis

Cited by 40 publications

References 7 publications

Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

Acceleration of de novo Cholesterol Synthesis in the Epidermis Influences Desquamation of the Stratum Corneum in Aged Mice

Significantly High Synthetic Activities of Cholesterol Sulfate in the Nasal, Oral and Tracheal Mucosae of Guinea Pigs

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