Abstract
Cornified cells of the stratum corneum have a monolayer of an unusual lipid covalently attached to the outer surface. This is referred to as the corneocyte lipid envelope (CLE). It consists of a monolayer of ω-hydroxyceramides covalently attached to the outer surface of the cornified envelope. The CLE is essential for proper barrier function of the skin and is derived from linoleate-rich acylglucosylceramides synthesized in the viable epidermis. Biosynthesis of acylglucosylceramide and its conversion to the cornified envelope is complex. Acylglucosylceramide in the bounding membrane of the lamellar granule is the precursor of the CLE. The acylglucosylceramide in the limiting membrane of the lamellar granule may be oriented with the glucosyl moiety on the inside. Conversion of the acylglucosylceramide to the CLE requires removal of the glucose by action of a glucocerebrosidase. The ester-linked fatty acid may be removed by an as yet unidentified esterase, and the resulting ω-hydroxyceramide may become ester linked to the outer surface of the cornified envelope through action of transglutaminase 1. Prior to removal of ester-linked fatty acids, linoleate is oxidized to an epoxy alcohol through action of 2 lipoxygenases. This can be further oxidized to an epoxy-enone, which can spontaneously attach to the cornified envelope through Schiff’s base formation. Mutations of genes coding for enzymes involved in biosynthesis of the CLE result in ichthyosis, often accompanied by neurologic dysfunction. The CLE is recognized as essential for barrier function of skin, but many questions about details of this essentiality remain. What are the relative roles of the 2 mechanisms of lipid attachment? What is the orientation of acylglucosylceramide in the bounding membrane of lamellar granules? Some evidence supports a role for CLE as a scaffold upon which intercellular lamellae unfold, but other evidence does not support this role. There is also controversial evidence for a role in stratum corneum cohesion. Evidence is presented to suggest that covalently bound ω-hydroxyceramides serve as a reservoir for free sphingosine that can serve in communicating with the viable epidermis and act as a potent broad-acting antimicrobial at the skin surface. Many questions remain.
References
1.
Gray
GM
, Yardley
HJ
. Lipid compositions of cells isolated from pig, human, and rat epidermis
. J Lipid Res
. 1975
;16
(6
):434
–40
.2.
Gray
GM
, Yardley
HJ
. Different populations of pig epidermal cells: isolation and lipid composition
. J Lipid Res
. 1975
;16
(6
):441
–7
.3.
Gray
GM
, White
RJ
. Glycosphingolipids and ceramides in human and pig epidermis
. J Invest Dermatol
. 1978
;70
(6
):336
–41
. .4.
Gray
GM
, White
RJ
, Major
JR
. 1-(3′-O-acyl)-beta-Glucosyl-N-dihydroxypentatriacontdienoylsphingosine, a major component of pig and human epidermis
. Biochim Piophys Acta
. 1978
;528
:127
–37
.5.
Wertz
PW
, Downing
DT
. Glycolipids in the epidermis: structure and function in the water barrier
. Science
. 1982
;217
:1261
–2
.6.
Wertz
PW
, Downing
DT
. Acylglucosylceramides of pig epidermis: structure determination
. J Lipid Res
. 1983
;24
(6
):753
–8
.7.
Wertz
PW
, Downing
DT
. Ceramides of pig epidermis: structure determination
. J Lipid Res
. 1983
;24
(6
):759
–65
.8.
Wertz
PW
, Downing
DT
. Glucosylceramides of pig epidermis: structure determination
. J Lipid Res
. 1983
;24
:1135
–9
.9.
Abraham
W
, Wertz
PW
, Downing
DT
. Linoleate-rich acylglucosylceramides of pig epidermis: structure determination by proton magnetic resonance
. J Lipid Res
. 1985
;26
(6
):761
–6
.10.
Bowser
PA
, Nugteren
DH
, White
RJ
, Houtsmuller
UM
, Prottey
C
. Identification, isolation and characterization of epidermal lipids containing linoleic acid
. Biochim Biophys Acta
. 1985
;834
(3
):419
–28
. .11.
Wertz
PW
, Downing
DT
. Covalently bound omega-hydroxyacylsphingosine in the stratum corneum
. Biochim Biophys Acta
. 1987
;917
(1
):108
–11
. .12.
Swartzendruber
DC
, Wertz
PW
, Madison
KC
, Downing
DT
. Evidence that the corneocyte has a chemically bound lipid envelope
. J Invest Dermatol
. 1987
;88
(6
):709
–13
. .13.
Kitajima
Y
, Sekiya
T
, Mori
S
, Nozawa
Y
, Yaoita
H
. Freeze-fracture cytochemical study of membrane systems in human epidermis using filipin as a probe for cholesterol
. J Invest Dermatol
. 1985
;84
(2
):149
–53
. .14.
Hedberg
CL
, Wertz
PW
, Downing
DT
. The time course of lipid biosynthesis in pig epidermis
. J Invest Dermatol
. 1988
;91
(2
):169
–74
. .15.
Starai
VJ
, Escalante-Semerena
JC
. Acetyl-coenzyme A synthetase (AMP forming)
. Cell Mol Life Sci
. 2004
;61
(16
):2020
–30
. .16.
Slabas
AR
, Brown
A
, Sinden
BS
, Swinhoe
R
, Simon
JW
, Ashton
AR
, et al. Pivotal reactions in fatty acid synthesis
. Prog Lipid Res
. 1994
;33
(1–2
):39
–46
. .17.
Brownsey
RW
, Zhande
R
, Boone
AN
. Isoforms of acetyl-CoA carboxylase: structures, regulatory properties and metabolic functions
. Biochem Soc Trans
. 1997
;25
(4
):1232
–8
. .18.
Smythe
CD
, Greenall
M
, Kealey
T
. The activity of HMG-CoA reductase and acetyl-CoA carboxylase in human apocrine sweat glands, sebaceous glands, and hair follicles is regulated by phosphorylation and by exogenous cholesterol
. J Invest Dermatol
. 1998
;111
(1
):139
–48
. .19.
Jones
SF
, Infante
JR
. Molecular pathways: fatty acid synthase
. Clin Cancer Res
. 2015
;21
(24
):5434
–8
. .20.
Chakravarty
B
, Gu
Z
, Chirala
SS
, Wakil
SJ
, Quiocho
FA
. Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain
. Proc Natl Acad Sci U S A
. 2004
;101
(44
):15567
–72
. .21.
Bar-Tana
J
, Rose
G
, Brandes
R
, Shapiro
B
. Palmitoyl-coenzyme A synthetase. Mechanism of reaction
. Biochem J
. 1973
;131
(2
):199
–209
. .22.
Ohno
Y
, Suto
S
, Yamanaka
M
, Mizutani
Y
, Mitsutake
S
, Igarashi
Y
, et al. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis
. Proc Natl Acad Sci U S A
. 2010
;107
(43
):18439
–44
. .23.
Jakobsson
A
, Westerberg
R
, Jacobsson
A
. Fatty acid elongases in mammals: their regulation and roles in metabolism
. Prog Lipid Res
. 2006
;45
(3
):237
–49
. .24.
Kihara
A
. Very long-chain fatty acids: elongation, physiology and related disorders
. J Biochem
. 2012
;152
(5
):387
–95
. .25.
Uchida
Y
. The role of fatty acid elongation in epidermal structure and function
. Dermatoendocrinol
. 2011
;3
(2
):65
–9
. .26.
Kitazawa
H
, Miyamoto
Y
, Shimamura
K
, Nagumo
A
, Tokita
S
. Development of a high-density assay for long-chain fatty acyl-CoA elongases
. Lipids
. 2009
;44
(8
):765
–73
. .27.
Agbaga
M-P
, Brush
RS
, Mandal
MNA
, Henry
K
, Elliott
MH
, Anderson
RE
. Role of stargard-3 macular dystrophy protein (ELOV4) in the biosynthesis of very long chain fatty acids
. Proc Natl Acad Sci U S A
. 2008
;105
:12843
–8
.28.
Nagao
K
, Murakami
A
, Umeda
M
. Structure and function of Δ9-fatty acid desaturase
. Chem Pharm Bull
. 2019
;67
(4
):327
–32
. .29.
Danso
M
, Boiten
W
, van Drongelen
V
, Gmelig Meijling
K
, Gooris
G
, El Ghalbzouri
A
, et al. Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition
. J Dermatol Sci
. 2017
;88
(1
):57
–66
. .30.
Dumas
SN
, Guo
CA
, Kim
JK
, Friedline
RH
, Ntambi
JM
. Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase-1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver
. Biochem Biophys Res Commun
. 2019
;508
(1
):87
–91
. .31.
Paton
CM
, Ntambi
JM
. Biochemical and physiological function of stearoyl-CoA desaturase
. Am J Physiol Endocrinol Metab
. 2009
;297
(1
):E28
–37
. .32.
Enoch
HG
, Catalá
A
, Strittmatter
P
. Mechanism of rat liver microsomal stearyl-CoA desaturase. Studies of the substrate specificity, enzyme-substrate interactions, and the function of lipid
. J Biol Chem
. 1976
;251
(16
):5095
–103
.33.
Downing
DT
, Colton
SW
. Skin surface lipids of the horse
. Lipids
. 1980
;15
(5
):323
–7
. .34.
Frost
ML
, Colton
SW
, Wertz
PW
, Downing
DT
. Structures of the dienoic lactones of horse sebum
. Comp Biochem Physiol B
. 1984
;78
(3
):549
–52
. .35.
Cameron
DJ
, Tong
Z
, Yang
Z
, Kaminoh
J
, Kamiyah
S
, Chen
H
, et al. Essential role of ELOVL4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival
. Int J Biol Sci
. 2007
;3
(2
):111
–9
. .36.
Hopiavuori
BR
, Anderson
RE
, Agbaga
M-P
. ELOV4: very long-chain fatty acids serve an eclectic role in mammalian health and function
. Prog Retinal Eye Res
. 2019
;69
:137
–58
.37.
Ohno
Y
, Nakamichi
S
, Ohkuni
A
, Kamiyama
N
, Naoe
A
, Tsujimura
H
, et al. Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation
. Proc Natl Acad Sci U S A
. 2015
;112
(25
):7707
–12
. .38.
Hall
AM
, Wiczer
BM
, Herrmann
T
, Stremmel
W
, Bernlohr
DA
. Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl-CoA synthetase activities in tissues from FATP4 null mice
. J Biol Chem
. 2005
;280
(12
):11948
–54
. .39.
Ohno
Y
. Elucidation of the synthetic mechanism of acylceramide, an essential lipid for skin barrier function
. Yakugaku Zasshi
. 2017
;137
(10
):1201
–8
. .40.
Yamamoto
H
, Hattori
M
, Chamulitrat
W
, Ohno
Y
, Kihara
A
. Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid ω-O-acylceramide
. Proc Natl Acad Sci U S A
. 2020
;117
(6
):2914
–22
. .41.
Radin
NS
. Biosynthesis of the sphingoid bases: a provocation
. J Lipid Res
. 1984
;25
(13
):1536
–40
.42.
Mizutani
Y
, Mitsutake
S
, Tsuji
K
, Kihara
A
, Igarashi
Y
. Ceramide biosynthesis in keratinocyte and its role in skin function
. Biochimie
. 2009
;91
(6
):784
–90
. .43.
Levy
M
, Futerman
AH
. Mammalian ceramide synthases
. IUBMB Life
. 2010
;62
(5
):347
–56
. .44.
Jennemann
R
, Rabionet
M
, Gorgas
K
, Epstein
S
, Dalpke
A
, Rothermel
U
, et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption
. Hum Mol Genet
. 2012
;21
(3
):586
–608
. .45.
Robson
KJ
, Stewart
ME
, Michelsen
S
, Lazo
ND
, Downing
DT
. 6-Hydroxy-4-sphingenine in human epidermal ceramides
. J Lipid Res
. 1994
;35
(11
):2060
–8
.46.
Madison
KC
, Sando
GN
, Howard
EJ
, True
CA
, Gilbert
D
, Swartzendruber
DC
, et al. Lamellar granule biogenesis: a role for ceramide glucosyltransferase, lysosomal enzyme transport, and the Golgi
. J Investig Dermatol Symp Proc
. 1998
;3
(2
):80
–6
. .47.
Ohno
Y
, Kamiyama
N
, Nakamichi
S
, Kihara
A
. PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide
. Nat Commun
. 2017
;8
:14610
. .48.
Hirabayashi
T
, Anjo
T
, Kaneko
A
, Senoo
Y
, Shibata
A
, Takama
H
, et al. PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis
. Nat Commun
. 2017
;8
:14609
. .49.
Grond
S
, Eichmann
TO
, Dubrac
S
, Kolb
D
, Schmuth
M
, Fischer
J
, et al. PNPLA1 deficiency in mice and humans leads to a defect in the synthesis of omega-O-acylceramides
. J Invest Dermatol
. 2017
;137
(2
):394
–402
. .50.
Klein
B
, Grond
S
, Haemmerie
G
, Lass
A
, Eichmann
TO
, Radner
FPW
. ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier
. J Lipid Res
. 2018
;59
:2360
–7
.51.
Wertz
PW
, Downing
DT
. Metabolism of linoleic acid in porcine epidermis
. J Lipid Res
. 1990
;31
(10
):1839
–44
.52.
Flammersfeld
A
, Panyot
A
, Yamaryo-Botté
Y
, Aurass
P
, Przyborski
JM
, Flieger
A
, et al. A patatin-like phospholipase functions during gametocyte induction in the malaria parasite Plasmodium falciparum
. Cell Microbiol
. 2020
;22
(3
):e13146
. .53.
Grayson
S
, Johnson-Winegar
AG
, Wintroub
BU
, Isseroff
RR
, Epstein
EH
, Elias
PM
. Lamellar body-enriched fractions from neonatal mice: preparative techniques and partial characterization
. J Invest Dermatol
. 1985
;85
(4
):289
–94
. .54.
Wertz
P
. Epidermal lamellar granules
. Skin Pharmacol Physiol
. 2018
;31
(5
):262
–8
. .55.
Sakai
K
, Akiyama
M
, Sugiyama-Nakagiri
Y
, McMillan
JR
, Sawamura
D
, Shimizu
H
. Localization of ABCA12 from Golgi apparatus to lamellar granules in human upper epidermal keratinocytes
. Exp Dermatol
. 2007
;16
(11
):920
–6
. .56.
Wertz
PW
, Downing
DT
, Freinkel
RK
, Traczyk
TN
. Sphingolipids of the stratum corneum and lamellar granules of fetal rat epidermis
. J Invest Dermatol
. 1984
;83
(3
):193
–5
. .57.
Raymond
AA
, Gonzalez de Peredo
A
, Stella
A
, Ishida-Yamamoto
A
, Bouyssie
D
, Serre
G
, et al. Lamellar bodies of human epidermis: proteomics characterization by high throughput mass spectrometry and possible involvement of CLIP-170 in their trafficking/secretion
. Mol Cell Proteomics
. 2008
;7
(11
):2151
–75
. .58.
Freinkel
RK
, Traczyk
TN
. Lipid composition and acid hydrolase content of lamellar granules of fetal rat epidermis
. J Invest Dermatol
. 1985
;85
(4
):295
–8
. .59.
60.
Elias
PM
, Fartasch
M
, Crumrine
D
, Behne
M
, Uchida
Y
, Holleran
WM
. Origin of the corneocyte lipid envelope (CLE): observations in Harlequin ichthyosis and cultured human keratinocytes
. J Invest Dermatol
. 2000
;115
(4
):765
–9
. .61.
Kelsell
DP
, Norgett
EE
, Unsworth
H
, Teh
MT
, Cullup
T
, Mein
CA
, et al. Mutations in ABCA12 underlie the severe congenital skin disease Harlequin ichthyosis
. Am J Hum Genet
. 2005
;76
(5
):794
–803
. .62.
Akayama
M
, Sugiyama-Nakagiri
Y
, Sakai
K
, McMillan
JR
, Goto
M
, Arita
K
, et al. Mutations in lipid transporter ABCA12 in Harlequin ichthyosis and functional recovery by corrective gene transfer
. J Clin Invest
. 2005
;115
:1777
–84
.63.
Wertz
PW
, Madison
KC
, Downing
DT
. Covalently bound lipids of human stratum corneum
. J Invest Dermatol
. 1989
;92
(1
):109
–11
. .64.
Chernomordik
LV
, Kozlov
MM
. Mechanics of membrane fusion
. Nat Struct Mol Biol
. 2008
;15
(7
):675
–83
. .65.
Slater
J
, Hill
JR
, Wertz
PW
. Evidence indicating that the acylglucosylceramide in the bounding membrane of lamellar granules is oriented with the glucosyl moiety on the inside
. J Dent Res
. 2003
;82A
:760
.66.
Landmann
L
, Wertz
PW
, Downing
DT
. Acylglucosylceramide causes flattening and stacking of liposomes. An analogy for assembly of the epidermal permeability barrier
. Biochim Biophys Acta
. 1984
;778
(3
):412
–8
. .67.
Abraham
W
, Wertz
PW
, Downing
DT
. Effect of epidermal acylglucosylceramides and acylceramides on the morphology of liposomes prepared from stratum corneum lipids
. Biochim Biophys Acta
. 1988
;939
(2
):403
–8
. .68.
Abraham
W
, Wertz
PW
, Downing
DT
. Fusion patterns of liposomes formed from stratum corneum lipids
. J Invest Dermatol
. 1988
;90
(3
):259
–62
. .69.
Norlen
L
. Skin barrier formation: the membrane folding model
. J Invest Dermatol
. 2001
;117
(4
):823
–9
. .70.
den Hollander
L
, Han
H
, de Winter
M
, Svensson
L
, Masich
S
, Daneholt
B
, et al. Skin lamellar bodies are not discrete vesicles but part of a tubuloreticular network
. Acta Derm Venereol
. 2016
;96
(3
):303
–8
. .71.
Norlen
L
. Skin barrier structure and function: the single gel phase model
. J Invert Dermatol
. 2001
;117
:830
–6
.72.
Narangifard
A
, den Hollander
L
, Wennberg
CL
, Lundborg
M
, Lindahl
E
, Iwai
I
, et al. Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryo-electron microscopy and EM-simulation
. Exp Cell Res
. 2018
;366
(2
):139
–51
. .73.
Brash
AR
, Yu
Z
, Boeglin
WE
, Schneider
C
. The hepoxilin connection in the epidermis
. FEBS J
. 2007
;274
(14
):3494
–502
. .74.
Munoz-Garcia
M
, Thomas
CP
, Keeney
DS
, Zheng
Y
, Brash
AR
. The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier
. Biochim Biophys Acta
. 2014
;1841
:401
–8
.75.
Simard-Bisson
C
, Parent
LA
, Moulin
VJ
, Fruteau de Laclos
B
. Characterization of epidermal lipoxygenase expression in normal human skin and tissue-engineered skin substitutes
. J Histochem Cytochem
. 2018
;66
(11
):813
–24
. .76.
Guneri
D
, Voegeli
R
, Munday
MR
, Lane
ME
, Rawlings
AV
. 12R-lipoxygenase activity is reduced in photodamaged facial stratum corneum: a novel activity assay indicates a key function in corneocyte maturation
. Int J Cosmet Sci
. 2019
;41
:274
–80
.77.
Yamanashi
H
, Boeglin
WE
, Morisseau
C
, Davis
RW
, Sulikowski
GA
, Hammock
BD
, et al. Catalytic activities of mammalian epoxide hydrolases with cis and trans fatty acid epoxides relevant to skin barrier function
. J Lipid Res
. 2018
;59
(4
):684
–95
. .78.
Chiba
T
, Thomas
CP
, Calcutt
MW
, Boeglin
WE
, O’Donnell
VB
, Brash
AR
. The precise structures and stereochemistry of trihydroxy-linoleates and their significance in barrier function. Implications of an epoxide hydrolase in the transformations of linoleate
. J Biol Chem
. 2016
;291
:14540
–54
.79.
Nugteren
DH
, Christ-Hazelhof
E
, van der Beek
A
, Houtsmuller
UM
. Metabolism of linoleic acid and other essential fatty acids in the epidermis of the rat
. Biochim Biophys Acta
. 1985
;834
(3
):429
–36
. .80.
Nemes
Z
, Marekov
LN
, Fésüs
L
, Steinert
PM
. A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation
. Proc Natl Acad Sci U S A
. 1999
;96
(15
):8402
–7
. .81.
Takuya
T
, Hirabayashi
T
, Miyasaka
Y
, Kawamoto
A
, Okuno
Y
, Taguchi
S
, et al. SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation
. J Clin Invest
. 2020
;130
:890
–903
.82.
Potts
RO
, Francoeur
ML
. The influence of stratum corneum morphology on water permeability
. J Invest Dermatol
. 1991
;96
(4
):495
–9
. .83.
Wertz
PW
, Madison
KC
, Downing
DT
. Covalently bound lipids of human stratum corneum
. J Invest Dermatol
. 1989
;92
(1
):109
–11
. .84.
Wertz
PW
, Downing
DT
. Stratum corneum: biological and biochemical considerations
. Drugs Pharm Sci
. 1989
;35
:1
–22
.85.
Madison
KC
, Swartzendruber
DC
, Wertz
PW
, Downing
DT
. Presence of intact intercellular lipid lamellae in the upper layers of the stratum corneum
. J Invest Dermatol
. 1987
;88
(6
):714
–8
. .86.
Swartzendruber
DC
, Wertz
PW
, Kitko
DJ
, Madison
KC
, Downing
DT
. Molecular models of the intercellular lipid lamellae in mammalian stratum corneum
. J Invest Dermatol
. 1989
;92
(2
):251
–7
. .87.
White
SH
, Mirejovsky
D
, King
GI
. Structure of lamellar lipid domains and corneocyte envelopes of murine stratum corneum. An X-ray diffraction study
. Biochemistry
. 1988
;27
(10
):3725
–32
. .88.
Bouwstra
JA
, Gooris
GS
, van der Spek
JA
, Bras
W
. Structural investigations of human stratum corneum by small-angle X-ray scattering
. J Invest Dermatol
. 1991
;97
(6
):1005
–12
. .89.
Hill
JR
, Wertz
PW
. Molecular models of the intercellular lipid lamellae from epidermal stratum corneum
. Biochim Biophys Acta
. 2003
;1616
(2
):121
–6
. .90.
Wertz
PW
, Swartzendruber
DC
, Kitko
DJ
, Madison
KC
, Downing
DT
. The role of the corneocyte lipid envelopes in cohesion of the stratum corneum
. J Invest Dermatol
. 1989
;93
(1
):169
–72
. .91.
Chapman
SJ
, Walsh
A
, Jackson
SM
, Friedmann
PS
. Lipids, proteins and corneocyte adhesion
. Arch Dermatol Res
. 1991
;283
(3
):167
–73
.92.
Crumrine
D
, Khnykin
D
, Krieg
P
, Man
MQ
, Celli
A
, Mauro
TM
, et al. Mutations in recessive congenital ichthyoses illuminate the origin and functions of the corneocyte lipid envelope
. J Invest Dermatol
. 2019
;139
(4
):760
–8
. .93.
Chang
F
, Swartzendruber
DC
, Wertz
PW
, Squier
CA
. Covalently bound lipids in keratinizing epithelia
. Biochim Biophys Acta
. 1993
;1150
(1
):98
–102
. .94.
Wertz
PW
, Downing
DT
. Ceramidase activity in porcine epidermis
. FEBS Lett
. 1990
;268
(1
):110
–2
. .95.
Yada
Y
, Higuchi
K
, Imokawa
G
. Purification and biochemical characterization of membrane-bound epidermal ceramidases from guinea pig skin
. J Biol Chem
. 1995
;270
(21
):12677
–84
. .96.
Houben
E
, Holleran
WM
, Yaginuma
T
, Mao
C
, Obeid
LM
, Rogiers
V
, et al. Differentiation-associated expression of ceramidase isoforms in cultured keratinocytes and epidermis
. J Lipid Res
. 2006
;47
(5
):1063
–70
. .97.
Wertz
PW
, Downing
DT
. Free sphingosines in porcine epidermis
. Biochim Biophys Acta
. 1998
;1002
(2
):213
–7
. .98.
Wertz
PW
, Downing
DT
. Free sphingosine in human epidermis
. J Invest Dermatol
. 1990
;94
(2
):159
–61
. .99.
Stewart
ME
, Downing
DT
. Free sphingosines of human skin include 6-hydroxysphingosine and unusually long-chain dihydrosphingosines
. J Invest Dermatol
. 1995
;105
(4
):613
–8
. .100.
Arikawa
J
, Ishibashi
M
, Kawashima
M
, Takagi
Y
, Ichikawa
Y
, Imokawa
G
. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus
. J Invest Dermatol
. 2002
;119
(2
):433
–9
. .101.
Fischer
CL
, Wertz
PW
. Effects of endogenous lipids on the skin microbiome
. In: Dayan
N
, editor. The skin microbiome: from basic research to product development
. Hoboken, NJ
: Wiley
; 2020
. p. 219
–35
.102.
Fischer
CL
, Drake
DR
, Dawson
DV
, Blanchette
DR
, Brogden
KA
, Wertz
PW
. Antibacterial activity of sphingoid bases and fatty acids against Gram-positive and Gram-negative bacteria
. Antimicrob Agents Chemother
. 2012
;56
(3
):1157
–61
. .103.
Bibel
DJ
, Aly
R
, Shah
S
, Shinefield
HR
. Sphingosines: antimicrobial barriers of the skin
. Acta Derm Venereol
. 1993
;73
(6
):407
–11
. .104.
Hannun
YA
, Loomis
CR
, Merrill
AH
, Bell
RM
. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets
. J Biol Chem
. 1986
;261
(27
):12604
–9
.105.
Steen Law
SL
, Squier
CA
, Wertz
PW
. Free sphingosine in oral epithelium
. Comp Biochem Physiol
. 1995
;110B
:511
–3
.106.
Hennings
H
, Elgjo
K
. Epidermal regeneration after cellophane tape stripping of hairless mouse skin
. Cell Tissue Kinet
. 1970
;3
(3
):243
–52
. .107.
Melton
JL
, Wertz
PW
, Swartzendruber
DC
, Downing
DT
. Effects of essential fatty acid deficiency on epidermal O-acylsphingolipids and transepidermal water loss in young pigs
. Biochim Biophys Acta
. 1987
;921
(2
):191
–7
. .108.
Weerheim
A
, Ponec
M
. Determination of stratum corneum lipid profile by tape stripping in combination with high-performance thin-layer chromatography
. Arch Dermatol Res
. 2001
;293
(4
):191
–9
. .109.
Radner
FP
, Marrakchi
S
, Kirchmeier
P
, Kim
GJ
, Ribierre
F
, Kamoun
B
, et al. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans
. PLoS Genet
. 2013
;9
(6
):e1003536
. .110.
Mueller
N
, Sassa
T
, Morales-Gonzalez
S
, Schneider
J
, Salchow
DJ
, Seelow
D
, et al. De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy
. J Med Genet
. 2019
;56
(3
):164
–75
. .111.
Kutkowska-Kazmierczak
A
, Rydzanicz
M
, Chlebowski
A
, Klosowska-Kosicka
K
, Mika
A
, Gruchota
J
, et al. Dominant ELOV1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features
. J Med Genet
. 2018
;55
:408
–14
.112.
Aldahmesh
MA
, Mohamed
JY
, Alkuraya
HS
, Verma
IC
, Puri
RD
, Alaiya
AA
, et al. Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia
. Am J Hum Genet
. 2011
;89
(6
):745
–50
. .113.
Agbaga
MP
. Different mutations in ELOVL4 affect very long chain fatty acid biosynthesis to cause variable neurological disorders in humans
. Adv Exp Med Biol
. 2016
;854
:129
–35
. .114.
Agbaga
MP
, Brush
RS
, Mandal
MN
, Henry
K
, Elliott
MH
, Anderson
RE
. Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids
. Proc Natl Acad Sci U S A
. 2008
;105
(35
):12843
–8
. .115.
Jobard
F
, Lefevre
C
, Karaduman
A
, Blanchet-Bardon
C
, Emre
S
, Weissenbach
J
, et al. Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX 12B) are mutated in non-bullous ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1
. Hum Mol Genet
. 2002
;11
:107
–13
.116.
Russel
LJ
, DiGiovanna
JJ
, Rogers
GR
, Steinert
PM
, Hashem
N
, Compton
JG
, et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis
. Nat Genet
. 1995
;9
:279
–83
.117.
Huber
M
, Rettler
I
, Bernasconi
K
, Frenk
E
, Lavrijsen
SP
, Ponec
M
, et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis
. Science
. 1995
;267
(5197
):525
–8
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