The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models

Richard W J Helder; Walter A Boiten; Rianne van Dijk; Gerrit S Gooris; Abdoelwaheb El Ghalbzouri; Joke A Bouwstra

doi:10.1016/j.bbalip.2019.158546

The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models

Richard W J Helder, Walter A Boiten, Rianne van Dijk, Gerrit S Gooris, Abdoelwaheb El Ghalbzouri, Joke A Bouwstra

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.

Original language	English
Article number	158546
Pages (from-to)	158546
Journal	Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Volume	1865
Issue number	2
DOIs	https://doi.org/10.1016/j.bbalip.2019.158546
Publication status	Published - Feb 2020
Externally published	Yes

Funding

This research was supported by the Dutch Technology Foundation STW (Grant 13151 ) and is part of the Netherlands Organization for Scientific Research (NWO). We also would like to thank the DUBBLE beam line BM26 staff at the European synchrotron radiation facility (Grenoble, France) for their support and the company Evonik for their supply of ceramides. Appendix A

Funders	Funder number
Netherlands Organization for Scientific Research
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Stichting voor de Technische Wetenschappen	13151

Keywords

Ceramides/metabolism
Culture Media/pharmacology
Dermatitis, Atopic/drug therapy
Drug Evaluation, Preclinical/methods
Fatty Acids, Nonesterified
Humans
Hydrocarbons, Fluorinated/pharmacology
Lipogenesis/drug effects
Liver X Receptors/agonists
Morphogenesis/drug effects
Primary Cell Culture/methods
Skin/drug effects
Stearoyl-CoA Desaturase/metabolism
Sulfonamides/pharmacology

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Helder, R. W. J., Boiten, W. A., van Dijk, R., Gooris, G. S., El Ghalbzouri, A., & Bouwstra, J. A. (2020). The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1865(2), 158546. Article 158546. https://doi.org/10.1016/j.bbalip.2019.158546

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title = "The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models",

abstract = "Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.",

keywords = "Ceramides/metabolism, Culture Media/pharmacology, Dermatitis, Atopic/drug therapy, Drug Evaluation, Preclinical/methods, Fatty Acids, Nonesterified, Humans, Hydrocarbons, Fluorinated/pharmacology, Lipogenesis/drug effects, Liver X Receptors/agonists, Morphogenesis/drug effects, Primary Cell Culture/methods, Skin/drug effects, Stearoyl-CoA Desaturase/metabolism, Sulfonamides/pharmacology",

author = "Helder, {Richard W J} and Boiten, {Walter A} and {van Dijk}, Rianne and Gooris, {Gerrit S} and {El Ghalbzouri}, Abdoelwaheb and Bouwstra, {Joke A}",

year = "2020",

month = feb,

doi = "10.1016/j.bbalip.2019.158546",

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volume = "1865",

pages = "158546",

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Helder, RWJ, Boiten, WA, van Dijk, R, Gooris, GS, El Ghalbzouri, A & Bouwstra, JA 2020, 'The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models', Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1865, no. 2, 158546, pp. 158546. https://doi.org/10.1016/j.bbalip.2019.158546

The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models. / Helder, Richard W J; Boiten, Walter A; van Dijk, Rianne et al.
In: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol. 1865, No. 2, 158546, 02.2020, p. 158546.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models

AU - Helder, Richard W J

AU - Boiten, Walter A

AU - van Dijk, Rianne

AU - Gooris, Gerrit S

AU - El Ghalbzouri, Abdoelwaheb

AU - Bouwstra, Joke A

PY - 2020/2

Y1 - 2020/2

N2 - Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.

AB - Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.

KW - Ceramides/metabolism

KW - Culture Media/pharmacology

KW - Dermatitis, Atopic/drug therapy

KW - Drug Evaluation, Preclinical/methods

KW - Fatty Acids, Nonesterified

KW - Humans

KW - Hydrocarbons, Fluorinated/pharmacology

KW - Lipogenesis/drug effects

KW - Liver X Receptors/agonists

KW - Morphogenesis/drug effects

KW - Primary Cell Culture/methods

KW - Skin/drug effects

KW - Stearoyl-CoA Desaturase/metabolism

KW - Sulfonamides/pharmacology

U2 - 10.1016/j.bbalip.2019.158546

DO - 10.1016/j.bbalip.2019.158546

M3 - Article

C2 - 31678517

SN - 1388-1981

VL - 1865

SP - 158546

JO - Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

JF - Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

IS - 2

M1 - 158546

ER -

The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models

Abstract

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Keywords

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