Glucosylated cholesterol in skin: Synthetic role of extracellular glucocerebrosidase

Boer, Daphne E.C.; Mirzaian, Mina; Ferraz, Maria J.; Nădăban, Andreea; Schreuder, Anne; Hovnanian, Alain; Smeden, Jeroen van; Bouwstra, Joke A.; Aerts, Johannes M. F. G.

doi:10.1016/j.cca.2020.09.017

Cited by 4 publications

(8 citation statements)

References 20 publications

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“…To the best of our knowledge, these acetylated colesterylsteryl glucosides which belong to the group of sterol lipids are sterol derivatives that have not been described in the context of atherosclerosis before. They belong to the complex group of glycolipids or steryl glycosides and are common plant phytosterol lipids [ 37 ] but also have been relatively recently found in various human tissues in significant amounts [ 4 ]. Here they serve, e.g., as storage forms of sterols but are also important for the physical stability of the cell membrane [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative lipid profiling of murine and human atherosclerotic plaques using high-resolution MALDI MSI

Khamehgir-Silz

Gerbig

Volk

et al. 2021

Pflugers Arch - Eur J Physiol

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The distribution of atherosclerotic lesions in the aorta and its branches of ApoE knockout (ApoE−/−) mice is like that of patients with atherosclerosis. By using high-resolution MALDI mass spectrometry imaging (MSI), we aimed at characterizing universally applicable physiological biomarkers by comparing the murine lipid marker profile with that of human atherosclerotic arteries. Therefore, the aorta or carotid artery of male ApoE−/− mice at different ages, human arteries with documented atherosclerotic changes originated from amputated limbs, and corresponding controls were analysed. Obtained data were subjected to multivariate statistical analysis to identify potential biomarkers. Thirty-one m/z values corresponding to individual lipid species of cholesterol esters, lysophosphatidylcholines, lysophosphatidylethanolamines, and cholesterol derivatives were found to be specific in aortic atherosclerotic plaques of old ApoE−/− mice. The lipid composition at related vessel positions of young ApoE−/− mice was more comparable with wild-type mice. Twenty-six m/z values of the murine lipid markers were found in human atherosclerotic peripheral arteries but also control vessels and showed a more patient-dependent diverse distribution. Extensive data analysis without marker preselection based on mouse data revealed lysophosphatidylcholine and glucosylated cholesterol species, the latter not being detected in the murine atherosclerotic tissue, as specific potential novel human atherosclerotic vessel markers. Despite the heterogeneous lipid profile of atherosclerotic peripheral arteries derived from human patients, we identified lipids specifically colocalized to atherosclerotic human tissue and plaques in ApoE−/− mice. These data highlight species-dependent differences in lipid profiles between peripheral artery disease and aortic atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Comparative lipid profiling of murine and human atherosclerotic plaques using high-resolution MALDI MSI

Khamehgir-Silz

Gerbig

Volk

et al. 2021

Pflugers Arch - Eur J Physiol

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“…11 Next to its role in formation of CER from GlcCER, GBA can catalyse transglucosylation reactions between GlcCER and cholesterol, resulting in formation of glucosylcholesterol (GlcChol) (Figure 1). 11,12 Levels of GlcChol in AD have not been investigated. Reduced expression or activity of GBA is associated with a reduced permeability barrier, 13 while inherited GBA deficiency leads to severe and life-threatening skin abnormalities such as those seen in the lysosomal storage disorder Gaucher disease.…”

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confidence: 99%

Children with atopic dermatitis show increased activity of β‐glucocerebrosidase and stratum corneum levels of glucosylcholesterol that are strongly related to the local cytokine milieu

et al. 2022

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Summary Background Atopic dermatitis (AD) is characterized by immune dysregulations and an impaired skin barrier, including abnormalities in lipid organization. In the stratum corneum (SC), β‐glucocerebrosidase (GBA) mediates transformation of glucosylceramide (GlcCER) into ceramide (CER) and cholesterol into glucosylcholesterol (GlcChol). Alteration in GBA activity might contribute to skin barrier defects in AD. Objectives To investigate GBA activity in the SC of children with AD before and after topical corticosteroid therapy and to compare it with healthy controls; to determine SC levels of GlcCER‐ and CER‐containing hydroxysphingosine base (GlcCER[H] and CER[H], respectively) and GlcChol; and to relate them to disease severity, skin barrier function and the local cytokine milieu. Methods Lipid markers and cytokines of innate, T helper 1 and T helper 2 immunity were determined in SC collected from healthy children and from clinically unaffected skin of children with AD, before and after 6 weeks of therapy with topical corticosteroids. AD severity was assessed by Scoring Atopic Dermatitis and skin barrier function by transepidermal water loss (TEWL). Results Baseline GBA activity and GlcChol levels were increased in children with AD but declined after therapy. CER[H] levels and the CER[H] to GlcCER[H] ratio were increased in AD. GBA activity and GlcChol correlated with TEWL and levels of multiple cytokines, especially interleukin‐1α and interleukin‐18. GlcChol was strongly associated with disease severity. Conclusions We show increased GBA activity and levels of GlcChol in AD. Our data suggest an important role of inflammation in disturbed lipid processing. GBA activity or GlcChol might be useful biomarkers in the monitoring of therapeutic responses in AD. What is already known about this topic? Patients with atopic dermatitis (AD) have a reduced skin barrier, mainly caused by altered lipid organization. The mechanisms underlying these lipid anomalies are not fully understood but likely reflect both genetic abnormalities in AD skin and the local cutaneous inflammatory environment. What does this study add? We show increased activity of the ceramide‐generating enzyme β‐glucocerebrosidase in AD. Activity of this enzyme was correlated with the local cytokine milieu and declined after local corticosteroid therapy. We show that glucosylcholesterol levels in the stratum corneum are increased in AD. The function of glucosylcholesterol and the physiological consequences of increased levels are not clear yet; however, its levels were strongly correlated with skin barrier function: high transepidermal water loss strongly correlated with high levels of glucosylcholesterol. What is the translational message? Correction of cutaneous inflammation largely restores alterations in lipid metabolism in the stratum corneum of infants with AD.

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“…We next investigated, by ABPP, the GBA/GBA2/GBA3 activity and selectivity of β‐ d ‐ xylo‐ cyclophellitol aziridine ABPs 6 and 8 in comparison to those of GBA‐specific ABP 9 [31] or ABP 10 . Surprisingly, the labeling pattern of GBA and GBA2 with xylo ‐cyclophellitol ABP 6 was very similar to that of the broad‐specific β‐ d ‐glucosidase ABP 10 (Figure 4 ): both probes label the two enzymes equally well, while ABP 6 labels GBA3 tenfold less efficiently than ABP 10 .…”

Section: Resultsmentioning

confidence: 99%

“…[ 29 , 30 ] In addition, GBA hydrolyses β‐ d ‐xylosides, including 4‐methylumbelliferyl‐β‐ d ‐xyloside and plant derived β‐ d ‐xylosides like cyanidin‐β‐ d ‐xyloside from plums and berries, as well as xylosylceramide. [31] GBA is also able to use β‐ d ‐xylosides as donors in transglycosylation reactions, generating xylosylcholesterol and di‐xylosylcholesterol. [32] In contrast to GBA, GBA2 is not active towards β‐ d ‐xylosides and the activity of GBA3 towards these substrates is very low.…”

Section: Introductionmentioning

confidence: 99%

Xylose‐Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase

Schröder

Lelieveld

et al. 2021

ChemBioChem

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Glucocerebrosidase (GBA), a lysosomal retaining β-d-glucosidase, has recently been shown to hydrolyze β-d-xylosides and to transxylosylate cholesterol. Genetic defects in GBA cause the lysosomal storage disorder Gaucher disease (GD), and also constitute a risk factor for developing Parkinson's disease. GBA and other retaining glycosidases can be selectively visualized by activity-based protein profiling (ABPP) using fluorescent probes composed of a cyclophellitol scaffold having a configuration tailored to the targeted glycosidase family. GBA processes β-dxylosides in addition to β-d-glucosides, this in contrast to the other two mammalian cellular retaining β-d-glucosidases, GBA2 and GBA3. Here we show that the xylopyranose preference also holds up for covalent inhibitors: xylose-configured cyclophellitol and cyclophellitol aziridines selectively react with GBA over GBA2 and GBA3 in vitro and in vivo, and that the xyloseconfigured cyclophellitol is more potent and more selective for GBA than the classical GBA inhibitor, conduritol B-epoxide (CBE). Both xylose-configured cyclophellitol and cyclophellitol aziridine cause accumulation of glucosylsphingosine in zebrafish embryo, a characteristic hallmark of GD, and we conclude that these compounds are well suited for creating such chemically induced GD models.

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Glucosylated cholesterol in skin: Synthetic role of extracellular glucocerebrosidase

Cited by 4 publications

References 20 publications

Comparative lipid profiling of murine and human atherosclerotic plaques using high-resolution MALDI MSI

Comparative lipid profiling of murine and human atherosclerotic plaques using high-resolution MALDI MSI

Children with atopic dermatitis show increased activity of β‐glucocerebrosidase and stratum corneum levels of glucosylcholesterol that are strongly related to the local cytokine milieu

Xylose‐Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase

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