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• W3171750785 abstract "Alterations of the lipid profile of the stratum corneum have an important role in the pathogenesis of atopic dermatitis (AD) because they contribute to epidermal barrier impairment. However, they have not previously been envisioned as a cellular response to altered metabolic requirements in AD epidermis. In this study, we report that the lipid composition in the epidermis of flaky tail, that is, ft/ft mice mimics that of human lesional AD (ADL) epidermis, both showing a shift toward shorter lipid species. The amounts of C24 and C26 free fatty acids and C24 and C26 ceramides—oxidized exclusively in peroxisomes—were reduced in the epidermis of ft/ft mice despite increased lipid synthesis, similar to that seen in human ADL edpidermis. Increased ACOX1 protein and activity in granular keratinocytes of ft/ft epidermis, altered lipid profile in human epidermal equivalents overexpressing ACOX1, and increased ACOX1 immunostaining in skin biopsies from patients with ADL suggest that peroxisomal β-oxidation significantly contributes to lipid signature in ADL epidermis. Moreover, we show that increased anaerobic glycolysis in ft/ft mouse epidermis is essential for keratinocyte proliferation and adenosine triphosphate synthesis but does not contribute to local inflammation. Thus, this work evidenced a metabolic shift toward enhanced peroxisomal β-oxidation and anaerobic glycolysis in ADL epidermis. Alterations of the lipid profile of the stratum corneum have an important role in the pathogenesis of atopic dermatitis (AD) because they contribute to epidermal barrier impairment. However, they have not previously been envisioned as a cellular response to altered metabolic requirements in AD epidermis. In this study, we report that the lipid composition in the epidermis of flaky tail, that is, ft/ft mice mimics that of human lesional AD (ADL) epidermis, both showing a shift toward shorter lipid species. The amounts of C24 and C26 free fatty acids and C24 and C26 ceramides—oxidized exclusively in peroxisomes—were reduced in the epidermis of ft/ft mice despite increased lipid synthesis, similar to that seen in human ADL edpidermis. Increased ACOX1 protein and activity in granular keratinocytes of ft/ft epidermis, altered lipid profile in human epidermal equivalents overexpressing ACOX1, and increased ACOX1 immunostaining in skin biopsies from patients with ADL suggest that peroxisomal β-oxidation significantly contributes to lipid signature in ADL epidermis. Moreover, we show that increased anaerobic glycolysis in ft/ft mouse epidermis is essential for keratinocyte proliferation and adenosine triphosphate synthesis but does not contribute to local inflammation. Thus, this work evidenced a metabolic shift toward enhanced peroxisomal β-oxidation and anaerobic glycolysis in ADL epidermis. Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder with a high prevalence worldwide. Although associations with genetic and environmental factors have been established, AD pathogenesis is still not fully understood (Czarnowicki et al., 2017Czarnowicki T. Krueger J.G. Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march.J Allergy Clin Immunol. 2017; 139: 1723-1734Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar; Guttman-Yassky et al., 2017Guttman-Yassky E. Waldman A. Ahluwalia J. Ong P.Y. Eichenfield L.F. Atopic dermatitis: pathogenesis.Semin Cutan Med Surg. 2017; 36: 100-103Crossref PubMed Scopus (26) Google Scholar; Leung and Guttman-Yassky, 2014Leung D.Y. Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches.J Allergy Clin Immunol. 2014; 134: 769-779Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Nevertheless, a defective epidermal barrier is likely involved in disease initiation (Kelleher et al., 2015Kelleher M. Dunn-Galvin A. Hourihane J.O. Murray D. Campbell L.E. McLean W.H.I. et al.Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year [retracted in J Allergy Clin Immunol 2021;147:1526].J Allergy Clin Immunol. 2015; 135: 930-935.e1Crossref PubMed Scopus (183) Google Scholar). Indeed, this defect is hypothesized to make the skin more vulnerable to environmental triggers such as allergens, microbes, or pollutants, which in turn elicit a local and humoral atopic immune response (Leung, 2016Leung D.Y.M. Clinical implications of new mechanistic insights into atopic dermatitis.Curr Opin Pediatr. 2016; 28: 456-462Crossref PubMed Scopus (24) Google Scholar; Leung and Guttman-Yassky, 2014Leung D.Y. Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches.J Allergy Clin Immunol. 2014; 134: 769-779Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Compensatory responses to the barrier impairment include keratinocyte (KC) hyperproliferation requiring lipid, DNA, and protein synthesis, which are all energy-intensive processes (Ajani et al., 2007Ajani G. Sato N. Mack J.A. Maytin E.V. Cellular responses to disruption of the permeability barrier in a three-dimensional organotypic epidermal model.Exp Cell Res. 2007; 313: 3005-3015Crossref PubMed Scopus (29) Google Scholar; Blunder et al., 2018Blunder S. Kõks S. Kõks G. Reimann E. Hackl H. Gruber R. et al.Enhanced expression of genes related to xenobiotic metabolism in the skin of patients with atopic dermatitis but not with ichthyosis vulgaris.J Invest Dermatol. 2018; 138: 98-108Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar; Proksch et al., 1993Proksch E. Holleran W.M. Menon G.K. Elias P.M. Feingold K.R. Barrier function regulates epidermal lipid and DNA synthesis.Br J Dermatol. 1993; 128: 473-482Crossref PubMed Scopus (197) Google Scholar). In AD, an overall decline in lipid content in the skin has been documented (Angelova-Fischer et al., 2011Angelova-Fischer I. Mannheimer A.C. Hinder A. Ruether A. Franke A. Neubert R.H. et al.Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling.Exp Dermatol. 2011; 20: 351-356Crossref PubMed Scopus (75) Google Scholar; Elias and Wakefield, 2014Elias P.M. Wakefield J.S. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 781-791.e1Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar; Proksch et al., 2003Proksch E. Jensen J.M. Elias P.M. Skin lipids and epidermal differentiation in atopic dermatitis.Clin Dermatol. 2003; 21: 134-144Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar; Schäfer and Kragballe, 1991Schäfer L. Kragballe K. Abnormalities in epidermal lipid metabolism in patients with atopic dermatitis.J Invest Dermatol. 1991; 96: 10-15Abstract Full Text PDF PubMed Scopus (98) Google Scholar) in association with dysregulated expression of genes controlling epidermal lipid metabolism (Blunder et al., 2018Blunder S. Kõks S. Kõks G. Reimann E. Hackl H. Gruber R. et al.Enhanced expression of genes related to xenobiotic metabolism in the skin of patients with atopic dermatitis but not with ichthyosis vulgaris.J Invest Dermatol. 2018; 138: 98-108Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar; Cole et al., 2014Cole C. Kroboth K. Schurch N.J. Sandilands A. Sherstnev A. O'Regan G.M. et al.Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 82-91Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Moreover, there is a clear shift toward shorter chain fatty acid (FA) and ceramide (Cer) species in the stratum corneum (SC) of patients with AD (Berdyshev et al., 2018Berdyshev E. Goleva E. Bronova I. Dyjack N. Rios C. Jung J. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (100) Google Scholar; Ishikawa et al., 2010Ishikawa J. Narita H. Kondo N. Hotta M. Takagi Y. Masukawa Y. et al.Changes in the ceramide profile of atopic dermatitis patients.J Invest Dermatol. 2010; 130: 2511-2514Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar; Janssens et al., 2012Janssens M. van Smeden J. Gooris G.S. Bras W. Portale G. Caspers P.J. et al.Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.J Lipid Res. 2012; 53: 2755-2766Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar; van Smeden et al., 2014bvan Smeden J. Janssens M. Kaye E.C. Caspers P.J. Lavrijsen A.P. Vreeken R.J. et al.The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.Exp Dermatol. 2014; 23: 45-52Crossref PubMed Scopus (144) Google Scholar), which contributes to aberrant lipid organization of the lamellar bilayers (Janssens et al., 2012Janssens M. van Smeden J. Gooris G.S. Bras W. Portale G. Caspers P.J. et al.Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.J Lipid Res. 2012; 53: 2755-2766Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). This is consistent with the altered content and secretion of lamellar bodies (LBs) observed in AD epidermis (Blunder et al., 2017Blunder S. Rühl R. Moosbrugger-Martinz V. Krimmel C. Geisler A. Zhu H. et al.Alterations in epidermal eicosanoid metabolism contribute to inflammation and impaired late differentiation in FLG-mutated atopic dermatitis.J Invest Dermatol. 2017; 137: 706-715Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar; Elias and Wakefield, 2014Elias P.M. Wakefield J.S. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 781-791.e1Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). However, these changes in lipid metabolism have not previously been envisioned as a cellular response to altered metabolic requirements in AD epidermis. To date, a thorough understanding of lipid and energy metabolism in KCs in AD is still missing. Previous work has shown that the dermal vasculature can supply the epidermis with nutrients, including glucose and FAs (Gherzi et al., 1992Gherzi R. Melioli G. de Luca M. D'Agostino A. Distefano G. Guastella M. et al.HepG2/erythroid/brain type glucose transporter (GLUT1) is highly expressed in human epidermis: keratinocyte differentiation affects GLUT1 levels in reconstituted epidermis.J Cell Physiol. 1992; 150: 463-474Crossref PubMed Scopus (39) Google Scholar; Grubauer et al., 1987Grubauer G. Feingold K.R. Elias P.M. Relationship of epidermal lipogenesis to cutaneous barrier function.J Lipid Res. 1987; 28: 746-752Abstract Full Text PDF PubMed Google Scholar; Khnykin et al., 2011Khnykin D. Miner J.H. Jahnsen F. Role of fatty acid transporters in epidermis: implications for health and disease.Dermatoendocrinol. 2011; 3: 53-61Crossref PubMed Scopus (46) Google Scholar; Zhang et al., 2018Zhang Z. Zi Z. Lee E.E. Zhao J. Contreras D.C. South A.P. et al.Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis.Nat Med. 2018; 24: 617-627Crossref PubMed Scopus (50) Google Scholar; Ziboh et al., 1986Ziboh V.A. Cohen K.A. Ellis C.N. Miller C. Hamilton T.A. Kragballe K. et al.Effects of dietary supplementation of fish oil on neutrophil and epidermal fatty acids. Modulation of clinical course of psoriatic subjects.Arch Dermatol. 1986; 122: 1277-1282Crossref PubMed Scopus (146) Google Scholar). However, the mode of energy metabolism used by KCs to fulfill their bioenergetic and biosynthetic needs in AD is still unknown. In this work, we investigated glycolysis and FA metabolism in lesional AD (ADL) epidermis. Moreover, we sought to determine whether the metabolic changes are a cause or a consequence of the disease. Flaky tail (ft/ft) mice are a model of ADL that harbor two gene mutations, that are, mutations of Flg and Tmem79 (Kypriotou et al., 2013Kypriotou M. Boéchat C. Huber M. Hohl D. Spontaneous atopic dermatitis-like symptoms in a/a ma ft/ma ft/J flaky tail mice appear early after birth.PLoS One. 2013; 8: e67869Crossref PubMed Scopus (8) Google Scholar; Moniaga et al., 2010Moniaga C.S. Egawa G. Kawasaki H. Hara-Chikuma M. Honda T. Tanizaki H. et al.Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus Extract.Am J Pathol. 2010; 176: 2385-2393Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar; Sasaki et al., 2013Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120.e4Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar; Saunders et al., 2013Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects [published correction appears in J Allergy Clin Immunol 2015;136:1710].J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). The skin of ft/ft mice displays impaired permeability barrier function, as measured by increased transepidermal water loss (TEWL) (Figure 1a) (Moniaga et al., 2010Moniaga C.S. Egawa G. Kawasaki H. Hara-Chikuma M. Honda T. Tanizaki H. et al.Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus Extract.Am J Pathol. 2010; 176: 2385-2393Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar; Saunders et al., 2013Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects [published correction appears in J Allergy Clin Immunol 2015;136:1710].J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), which is also observed in human ADL skin regardless of disease severity, in contrast to nonlesional AD skin (Seidenari and Giusti, 1995Seidenari S. Giusti G. Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin.Acta Derm Venereol. 1995; 75: 429-433PubMed Google Scholar; Yazdanparast et al., 2019Yazdanparast T. Yazdani K. Humbert P. Khatami A. Nasrollahi S.A. Firouzabadi L.I. et al.Biophysical measurements and ultrasonographic findings in chronic dermatitis in comparison with uninvolved skin.Indian J Dermatol. 2019; 64: 90-96Crossref PubMed Google Scholar). To validate ft/ft mice as a model of ADL with respect to lipid composition, we first studied the chain length distribution in (i) epidermal Cers containing a C18 sphingosine base linked to a nonhydroxy FA (i.e., Cer[NS]), (ii) free FAs (FFAs), and (iii) very long chain, ester-linked ω-O-acylCers (i.e., Cer[EO]). We found that ft/ft mouse epidermis has a marked increase in the relative levels of Cer(NS)-containing C16–C22 FA moieties and a decrease in those harboring C24 and C26 very-long-chain fatty acid (VLCFA) moieties, whereas total Cer(NS) content remained unchanged (Figure 1b and c). Similarly, ω-O-acylCers contained diminished levels of 53:3 and 54:3 species and increased levels of several species with shorter chain lengths, without significant changes in the total amounts (Figure 1d and e). Thus, our data reveal alterations in Cer classes in the epidermis of ft/ft mice similar to those described in human ADL (Berdyshev et al., 2018Berdyshev E. Goleva E. Bronova I. Dyjack N. Rios C. Jung J. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (100) Google Scholar; Ishikawa et al., 2010Ishikawa J. Narita H. Kondo N. Hotta M. Takagi Y. Masukawa Y. et al.Changes in the ceramide profile of atopic dermatitis patients.J Invest Dermatol. 2010; 130: 2511-2514Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar; Janssens et al., 2012Janssens M. van Smeden J. Gooris G.S. Bras W. Portale G. Caspers P.J. et al.Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.J Lipid Res. 2012; 53: 2755-2766Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar; van Smeden et al., 2014bvan Smeden J. Janssens M. Kaye E.C. Caspers P.J. Lavrijsen A.P. Vreeken R.J. et al.The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.Exp Dermatol. 2014; 23: 45-52Crossref PubMed Scopus (144) Google Scholar). Moreover, the relative amounts of saturated FAs with 20–22 carbon atoms were higher and amounts of those with 26 carbon atoms were lower in the epidermis of ft/ft mice than in the epidermis of control mice (Figure 1f). Furthermore, consistent with previous observations on SC or epidermal specimens of ADL (Schäfer and Kragballe, 1991Schäfer L. Kragballe K. Abnormalities in epidermal lipid metabolism in patients with atopic dermatitis.J Invest Dermatol. 1991; 96: 10-15Abstract Full Text PDF PubMed Scopus (98) Google Scholar; van Smeden et al., 2014bvan Smeden J. Janssens M. Kaye E.C. Caspers P.J. Lavrijsen A.P. Vreeken R.J. et al.The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.Exp Dermatol. 2014; 23: 45-52Crossref PubMed Scopus (144) Google Scholar), we found higher total levels of monounsaturated FAs in the epidermis of ft/ft mice than those in the epidermis of control mice, in contrast to the total levels of saturated FAs (Figure 1g). Shortening of the FA moiety in Cers has been shown to alter the formation of SC lamellar bilayers, a process initiated in LBs (Feingold and Elias, 2014Feingold K.R. Elias P.M. Role of lipids in the formation and maintenance of the cutaneous permeability barrier.Biochim Biophys Acta. 2014; 1841: 280-294Crossref PubMed Scopus (211) Google Scholar; Janssens et al., 2012Janssens M. van Smeden J. Gooris G.S. Bras W. Portale G. Caspers P.J. et al.Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.J Lipid Res. 2012; 53: 2755-2766Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar; van Smeden et al., 2014bvan Smeden J. Janssens M. Kaye E.C. Caspers P.J. Lavrijsen A.P. Vreeken R.J. et al.The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.Exp Dermatol. 2014; 23: 45-52Crossref PubMed Scopus (144) Google Scholar). Ultrastructural analysis showed LBs to be scarce, empty, or filled with inhomogeneous material and to exhibit altered morphology in the epidermis of ft/ft mice, indicating abnormal cargo composition and altered lamellar bilayers in the SC (Figure 1h), as reported earlier (Scharschmidt et al., 2009Scharschmidt T.C. Man M.Q. Hatano Y. Crumrine D. Gunathilake R. Sundberg J.P. et al.Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol. 2009; 124: 496-506.e1–6Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Thus, abnormalities of epidermal lipid composition and of the LB secretory system in ft/ft mice largely mimic those observed in human ADL (Berdyshev et al., 2018Berdyshev E. Goleva E. Bronova I. Dyjack N. Rios C. Jung J. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (100) Google Scholar; Blunder et al., 2017Blunder S. Rühl R. Moosbrugger-Martinz V. Krimmel C. Geisler A. Zhu H. et al.Alterations in epidermal eicosanoid metabolism contribute to inflammation and impaired late differentiation in FLG-mutated atopic dermatitis.J Invest Dermatol. 2017; 137: 706-715Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar; Elias and Wakefield, 2014Elias P.M. Wakefield J.S. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 781-791.e1Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar; Ishikawa et al., 2010Ishikawa J. Narita H. Kondo N. Hotta M. Takagi Y. Masukawa Y. et al.Changes in the ceramide profile of atopic dermatitis patients.J Invest Dermatol. 2010; 130: 2511-2514Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar; Janssens et al., 2012Janssens M. van Smeden J. Gooris G.S. Bras W. Portale G. Caspers P.J. et al.Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.J Lipid Res. 2012; 53: 2755-2766Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar; van Smeden et al., 2014bvan Smeden J. Janssens M. Kaye E.C. Caspers P.J. Lavrijsen A.P. Vreeken R.J. et al.The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.Exp Dermatol. 2014; 23: 45-52Crossref PubMed Scopus (144) Google Scholar). To better understand the origin of the abnormal lipid composition in ADL, we examined the expression of 86 genes involved in lipid metabolism using microarray analysis. We found that genes involved in long-chain FA oxidation, activation, and trafficking were among the most strongly upregulated in the epidermis of ft/ft mice when compared with the epidermis of control mice (Figure 2a). In contrast, the expression of several genes involved in long-chain FA import into cells (Fabp3, Slc27a1, Slc27a2, Slc27a5, Cd36, Acsl3), and peroxisome proliferator–activated receptor (PPAR) signaling (e.g., Ppara, Pparg, Cpt1a, Apoc3, Apoe) was downregulated in the epidermis of ft/ft mice when compared with the epidermis of control mice (Figure 2a). qPCR confirmed increased mRNA level of Acox1 (an enzyme catalyzing the oxidation of straight-chain VLCFAs and ultra long-chain FAs [ULCFAs] in peroxisomes) and of Hsd17b4 (an enzyme participating in the second step of peroxisomal VLCFA oxidation [Baes et al., 2000Baes M. Huyghe S. Carmeliet P. Declercq P.E. Collen D. Mannaerts G.P. et al.Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids.J Biol Chem. 2000; 275: 16329-16336Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]) in the epidermis of ft/ft mice when compared with the epidermis of the controls (Figure 2b). Moreover, ACOX1 was induced at the protein level, mainly in the upper spinous and granular layers of ft/ft mouse epidermis (Figure 2c and d). Furthermore, we measured ACOX enzymatic activity by following the production rate of hydrogen peroxide after the addition of very-long-chain fatty acyl-coenzyme As (CoAs) (Vamecq, 1990Vamecq J. Fluorometric assay of peroxisomal oxidases.Anal Biochem. 1990; 186: 340-349Crossref PubMed Scopus (36) Google Scholar). 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Results revealed a significant increase in the oxidation of both fatty acyl-CoA species in epidermal bulk cells of ft/ft mice compared with that in the epidermal bluk cells of the controls (Figure 2e). Thus, peroxisomal oxidation of VLCFAs is enhanced in ft/ft mouse epidermis. In line with this observation, we found increased expression levels of Acot5 and Acot8 (Figure 2f), genes encoding two acyl-CoA thioesterases involved in downstream steps of peroxisomal FA oxidation (Westin et al., 2005Westin M.A. Hunt M.C. Alexson S.E. The identification of a succinyl-CoA thioesterase suggests a novel pathway for succinate production in peroxisomes.J Biol Chem. 2005; 280: 38125-38132Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), as well as the expression level of Crot, encoding a carnitine octanoyltransferase responsible for the transport of shortened FAs out of peroxisomes (Figure 2g) (Wanders et al., 2016Wanders R.J. Waterham H.R. Ferdinandusse S. Metabolic interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum.Front Cell Dev Biol. 2016; 3: 83Crossref PubMed Scopus (141) Google Scholar; Westin et al., 2008Westin M.A. Hunt M.C. Alexson S.E. Short- and medium-chain carnitine acyltransferases and acyl-CoA thioesterases in mouse provide complementary systems for transport of beta-oxidation products out of peroxisomes.Cell Mol Life Sci. 2008; 65: 982-990Crossref PubMed Scopus (52) Google Scholar). Thus, in a context where FA uptake is not coordinated to sustained peroxisomal lipid oxidation, VLCFAs/ULCFAs might not be sufficiently packed into LBs and integrated into structural lipids such as Cers, thereby potentially explaining the shift toward the shorter acyl chain lengths of Cers and FFAs in ft/ft mouse epidermis. PPARs are master regulators of lipid homeostasis, and reduced levels of PPARA and PPARG have been consistently observed in ADL (Plager et al., 2007Plager D.A. Leontovich A.A. Henke S.A. Davis M.D. McEvoy M.T. Sciallis 2nd, G.F. et al.Early cutaneous gene transcription changes in adult atopic dermatitis and potential clinical implications.Exp Dermatol. 2007; 16: 28-36Crossref PubMed Scopus (49) Google Scholar; Töröcsik et al., 2019Töröcsik D. Weise C. Gericke J. Szegedi A. Lucas R. Mihaly J. et al.Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non-affected skin of human atopic dermatitis patients.Exp Dermatol. 2019; 28: 177-189Crossref PubMed Scopus (16) Google Scholar), whereas data on PPARD have not been reported. We found selective upregulation of Ppard expression in ft/ft mouse epidermis compared with that in control epidermis, as opposed to the expression of Ppara and Pparg (Figure 2a and h). In mouse KCs, Ppard expression has been shown to be upregulated by TNF-α (Michalik et al., 2003Michalik L. Desvergne B. Wahli W. Peroxisome proliferator-activated receptors beta/delta: emerging roles for a previously neglected third family member.Curr Opin Lipidol. 2003; 14: 129-135Crossref PubMed Scopus (59) Google Scholar) and IL-1β (Blunder et al., 2021Blunder S. Krimbacher T. Moosbrugger-Martinz V. Gruber R. Schmuth M. Dubrac S. Keratinocyte-derived IL-1β induces PPARG downregulation and PPARD upregulation in human reconstructed epidermis following barrier impairment [e-pub ahead of print].Exp Dermatol. 2021; (accessed 19 July 2021)https://doi.org/10.1111/exd.14323Crossref PubMed Scopus (3) Google Scholar), cytokines increased in the epidermis of ft/ft mice (Figure 3a and b), likely in response to the impaired epidermal barrier (Tsai et al., 1994Tsai J.C. Feingold K.R. Crumrine D. Wood L.C. Grunfeld C. Elias P.M. Permeability barrier disruption alters the localization and expression of TNF alpha/protein in the epidermis.Arch Dermatol Res. 1994; 286: 242-248Crossref PubMed Scopus (80) Google Scholar; Wood et al., 1992Wood L.C. Jackson S.M. Elias P.M. Grunfeld C. Feingold K.R. Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice.J Clin Invest. 1992; 90: 482-487Crossref PubMed Scopus (395) Google Scholar). FABP5 has been shown to translocate to the nucleus to deliver ligands specifically to PPARδ and to be a PPARδ target gene (Schug et al., 2008Schug T.T. Berry D.C. Toshkov I.A. Cheng L. Nikitin A.Y. Noy N. Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARbeta/delta to RAR.Proc Natl Acad Sci USA. 2008; 105: 7546-7551Crossref PubMed Scopus (134) Google Scholar; Tan et al., 2002Tan N.S. Shaw N.S. Vinckenbosch N. Liu P. Yasmin R. Desvergne B. et al.Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription [published correction appears in Mol Cell Biol 2002;22:6318].Mol Cell Biol. 2002; 22: 5114-5127Crossref PubMed Scopus (385) Google Scholar). FABP5 was increased at both protein and mRNA levels (Figure 3c and d) and mainly localized to suprabasal KC nuclei in the epidermis of ft/ft mice compared with those in the epidermis of the controls (Figure 3e). Thus, enhanced PPARδ signaling might promote peroxisomal oxidation of VLCFAs/ULCFAs in ft/ft mouse epidermis by the upregulation of ACOX1 (Higgins et al., 2012Higgins L.G. Garbacz W.G. Gustafsson M.C. Nainamalai S. Ashby P.R. W" @default.
• W3171750785 created "2021-06-22" @default.
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• W3171750785 date "2021-09-01" @default.
• W3171750785 modified "2023-10-03" @default.
• W3171750785 title "Peroxisomal Fatty Acid Oxidation and Glycolysis Are Triggered in Mouse Models of Lesional Atopic Dermatitis" @default.
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