Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action

Nelson, Amanda M.; Zhao, Wei; Gilliland, Kathryn L.; Zaenglein, Andrea L.; Liu, Wenlei; Thiboutot, Diane

doi:10.4161/derm.1.3.8258

Cited by 46 publications

(38 citation statements)

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“…Isotretinoin treatment causes apoptosis and reduced size of the sebaceous gland, and the sebocytes appear undifferentiatied and have decreased lipid accumulation [2], [73]. We propose that the elevated levels of all- trans retinoic acid in the skin of SKO mice leads to sebaceous gland dysfunction.…”

Section: Discussionmentioning

confidence: 88%

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Metabolic Changes in Skin Caused by Scd1 Deficiency: A Focus on Retinol Metabolism

et al. 2011

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We previously reported that mice with skin-specific deletion of stearoyl-CoA desaturase-1 (Scd1) recapitulated the skin phenotype and hypermetabolism observed in mice with a whole-body deletion of Scd1. In this study, we first performed a diet-induced obesity experiment at thermoneutral temperature (33°C) and found that skin-specific Scd1 knockout (SKO) mice still remain resistant to obesity. To elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin phenotype, we performed microarray analysis of skin gene expression in male SKO and control mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebaceous gland hypoplasia, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXRα. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. Furthermore, SEB-1 sebocytes treated with retinol and SCD inhibitor also display an elevation in retinoic acid-induced genes. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin phenotype.

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Section: Discussionmentioning

confidence: 88%

“…Skin biopsies taken from patients treated with isotretinoin also showed high expression of LCN2 (lipocalin-2) [57], [73]. Additionally, isotretinoin treatment of SEB-1 human sebocyte cultures causes cell cycle arrest and apoptosis concomitant with increased expression of LCN2 [72], [74].…”

Section: Discussionmentioning

confidence: 98%

Metabolic Changes in Skin Caused by Scd1 Deficiency: A Focus on Retinol Metabolism

et al. 2011

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“…Currently, DNA microarrays are mainly used for genotyping (6)(7)(8)(9), gene expression profiling (10)(11)(12) and microRNA screening (13)(14)(15). In medicine, microarrays are used to determine the complexity and heterogeneity of diseases, to facilitate disease classification and to predict therapeutic outcomes (8,(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Analysis of boutique arrays: A universal method for the selection of the optimal data normalization procedure

Uszczyńska

Zyprych-Walczak

Handschuh

et al. 2013

International Journal of Molecular Medicine

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Abstract. DNA microarrays, which are among the most popular genomic tools, are widely applied in biology and medicine. Boutique arrays, which are small, spotted, dedicated microarrays, constitute an inexpensive alternative to whole-genome screening methods. The data extracted from each microarray-based experiment must be transformed and processed prior to further analysis to eliminate any technical bias. The normalization of the data is the most crucial step of microarray data pre-processing and this process must be carefully considered as it has a profound effect on the results of the analysis. Several normalization algorithms have been developed and implemented in data analysis software packages. However, most of these methods were designed for whole-genome analysis. In this study, we tested 13 normalization strategies (ten for double-channel data and three for single-channel data) available on R Bioconductor and compared their effectiveness in the normalization of four boutique array datasets. The results revealed that boutique arrays can be successfully normalized using standard methods, but not every method is suitable for each dataset. We also suggest a universal seven-step workflow that can be applied for the selection of the optimal normalization procedure for any boutique array dataset. The described workflow enables the evaluation of the investigated normalization methods based on the bias and variance values for the control probes, a differential expression analysis and a receiver operating characteristic curve analysis. The analysis of each component results in a separate ranking of the normalization methods. A combination of the ranks obtained from all the normalization procedures facilitates the selection of the most appropriate normalization method for the studied dataset and determines which methods can be used interchangeably. IntroductionDespite the dynamic development of deep sequencing technologies, microarrays are still commonly used in genomic research (1-5). Currently, DNA microarrays are mainly used for genotyping (6-9), gene expression profiling (10-12) and microRNA screening (13-15). In medicine, microarrays are used to determine the complexity and heterogeneity of diseases, to facilitate disease classification and to predict therapeutic outcomes (8,(16)(17)(18)(19)(20)(21)(22).Microarrays provide a large amount of useful information, but are accompanied by inherent noise and systematic errors (23)(24)(25)(26). No microarray experiment is free from variation introduced during sample preparation, hybridization, washing and scanning (24,27,28). Spotted arrays are burdened with technical defects that occur during their printing; these defects manifest as differences in spot size and shape and/or shifts of spots, rows or whole print-tips (24,28). In two-color assays, additional bias is introduced by uneven dye incorporation and by differences in the signal dynamic range and the sensitivity of dyes to photobleaching (23,24,29). Therefore, the major challenge in microarray analysis is data pr...

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“…In einer aktuellen Untersuchung zur Modulation der Genexpression von Aknepatienten unter Isotretinoin-Therapie zeigten sich u. a. Veränderungen von Genen, die für das Matrixremodeling verantwortlich sind [16], welches auch bei der Rosazea pathologisch verändert ist. Weiterhin hat Isotretinoin potente antifibrotische Effekte in vivo [1] und moduliert die Expression der Matrixmetalloproteasen in Keratinozyten [21].…”

Section: Introductionunclassified

“…Hemmung des Kollagenund Matrixabbaus, antifibrotischer Effekt, Modulation des Remodelings Induktion von Kollagen, Fibronektin, bestimmter Matrixmetalloproteasen[16,21] …”

unclassified

Rosazea

Thielitz

Gollnick

2011

Hautarzt

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Systemic isotretinoin has been known for decades as an effective and safe therapeutic option in the treatment of severe and refractory forms of rosacea. It can also be used in special treatment-resistant forms of rosacea, e.g. granulomatous rosacea, as efficacious second-line therapy. Previously, the effect of isotretinoin in rosacea has been mainly studied in small cohorts or anecdotal reports. Recently, a big randomized double-blind dose-response and comparative study revealed that an optimized dosage of 0,3 mg/kg was superior to other dosages and non-inferior to doxycycline as gold standard of systemic rosacea treatment and proved effective and safe in papulopustular and phymatous subtypes. However, the substance is still not licensed for this indication The efficacy of isotretinoin in rosacea is probably mainly related to anti-inflammatory mechanisms as well as anti-oxidative, anti-angiogenic and antifibrotic properties. The classical antiseborrheic effect of isotretinoin might play a role in special subtypes like the phymatous type or rosacea fulminans.

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Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action

Cited by 46 publications

References 35 publications

Metabolic Changes in Skin Caused by Scd1 Deficiency: A Focus on Retinol Metabolism

Metabolic Changes in Skin Caused by Scd1 Deficiency: A Focus on Retinol Metabolism

Analysis of boutique arrays: A universal method for the selection of the optimal data normalization procedure

Rosazea

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