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REVIEW ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 1  |  Page : 6-9

Liver X receptor α: does it have a role in the pathogenesis of vitiligo?


1 Department of Dermatology, Faculty of Medicine, Menoufia University, Minufya, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University, Minufya, Egypt
3 Residant Doctor of Dermatology, Kafr El-Sheikh Health Sector, Metoubes, Egypt

Date of Submission09-Sep-2016
Date of Acceptance04-Oct-2016
Date of Web Publication25-Jul-2017

Correspondence Address:
Sherin M Atallah
Motobes, Kafr El-Sheikh, Metoubes, 33511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.211507

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  Abstract 


The aim of the work was to highlight liver X receptor α (LXR-α) and its role in the pathogenesis of vitiligo. Data were obtained from medical text books, medical journals, and medical websites, which had updated investigations with the keywords (liver X receptors and vitiligo) in the title of the papers. Selection was carried out by supervisors for studying LXR-α and its role in the pathogenesis of vitiligo. A special search was carried out for the keywords liver X receptors and vitiligo in the title of the papers. Extraction was carried out and included assessment of the quality and validity of papers that met with the prior criteria described in the review. The main result of the review and each study was reviewed independently. The obtained data were translated into a new language based on the need of the researcher and have been presented in various sections throughout the article. We now know that LXR-α plays an important role in the pathogenesis of vitiligo through its effect on melanogenesis and also through its role in keratinocyte proliferation and apoptosis that affect growth and/or melanization of surrounding melanocytes. In total 54 potentially relevant publications were included, 34 were human and 20 were animal studies. The studies indicate an association between LXR-α and vitiligo pathogenesis as LXRs affect melanogenesis through its effect on genes involved in melanogenesis and also through its role on keratinocyte death, which leads to a decrease in several keratinocyte-derived mediators and growth factors supporting the growth and/or melanization of surrounding melanocytes.

Keywords: liver X receptors, pathogenesis, vitiligo


How to cite this article:
Shoeib MA, Bakry OA, Nor-EldinnElkady NM, Atallah SM. Liver X receptor α: does it have a role in the pathogenesis of vitiligo?. Menoufia Med J 2017;30:6-9

How to cite this URL:
Shoeib MA, Bakry OA, Nor-EldinnElkady NM, Atallah SM. Liver X receptor α: does it have a role in the pathogenesis of vitiligo?. Menoufia Med J [serial online] 2017 [cited 2017 Oct 22];30:6-9. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/6/211507




  Introduction Top


Vitiligo is a relatively common, probably autoimmune disorder that affects people of all backgrounds and both sexes. No particular group seems to be preferentially affected [1].

Vitiligo is characterized by irregularly shaped white patches on the skin. It is more noticeable in darker-skinned people because of the contrast of white patches against dark skin [2].

Several theories were suggested to explain vitiligo pathogenesis. The main principles of all are the absence of functional melanocytes in vitiligo skin and loss of histochemically recognized melanocytes, owing to their destruction. However, the destruction is most likely a slow process resulting in a progressive decrease in melanocytes. Theories on destruction of melanocytes include autoimmune mechanisms, cytotoxic mechanisms, an intrinsic defect of melanocytes, oxidant–antioxidant mechanisms, and neural mechanisms [3].

Research at the molecular level has demonstrated a deficiency of antioxidant substances in vitiliginous skin. This leads to the cytotoxic action of reactive oxygen species such as superoxide anion and hydroxyl radical, which are generated by the ultraviolet-damaged epidermis. The free radicals are also cytotoxic to melanocytes and inhibit tyrosinase [4]. Zinc is considered an antioxidant because of the dependency of the extracellular enzyme superoxide dismutase on zinc. Zinc plays a vital role in the protection against free radical damage and takes part in the process of melanogenesis. A low level of serum zinc is a significant risk factor for vitiligo [4].

Most studies on vitiligo have concentrated on the abnormality of melanocytes rather than the abnormality of keratinocytes; however, epidermal melanocytes form a functional and structural unit with neighboring keratinocytes [5].

The liver X receptors (LXRs) including LXR-α and LXR-β are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors [6].

In recent times, the role of LXRs in skin physiology and pathology has evolved rapidly because of their effect on cellular proliferation and differentiation together with its role in carcinogenesis [7].

LXR-α and LXR-β are expressed in sebaceous glands, sweat glands, and hair follicles [8]. Furthermore, both LXR-α and LXR-β are expressed in cultured human keratinocytes and throughout all layers of the human epidermis [7]. A marked expression of LXR-α has been observed in cells adjacent to dermal papilla, speculating that it may correlate with the site of hair melanocytes [8]. In the skin, activation of LXRs stimulates the differentiation of keratinocytes and augments lipid synthesis in sebocytes [9].

Important genes involved in the regulation of melanocyte functions are target genes of LXRs. It can be speculated that LXRs might be playing an important role in the pathogenesis of pigmentary disorders including vitiligo, and hence they may provide promising drug targets for the treatment [10].


  Materials and Methods Top


Search strategy

We reviewed papers on the role of LXR-α in vitiligo pathogenesis from Medline databases (PubMed, Medscape, and ScienceDirect) and also from material available on the internet. We used liver X receptors and pathogenesis of vitiligo as search terms. In addition, the search was performed in the electronic databases from 1996 to 2016.

Study selection

All studies were independently assessed for inclusion criteria. They were included if they fulfilled the following criteria:

  • Published in English language
  • Published in peer-reviewed journals
  • Focused on vitiligo pathogenesis
  • Discussed the role of LXRs in the pathogenesis of vitiligo
  • If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.


Data extraction

Studies that did not fulfill the above criteria and reports without peer-review, letters/comments/editorials/news were excluded.

The publications analyzed were evaluated according to evidence-based medicine criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for evidence-based medicine in addition to the evidence pyramid.

US Preventive Services Task Force:

Level I: Evidence obtained from at least one properly designed randomized controlled trial.

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from a well-designed cohort or case–control analytical studies, preferably from more than one center or research group.

Level II-3: Evidence obtained from multiple time series with or without intervention. Significant results in uncontrolled trials might also be regarded as this type of evidence.

Level III: Opinions of respected authorities, on the basis of clinical experience, descriptive studies, or reports of expert committees.

Quality assessment

The quality of all studies was assessed. Important factors included the study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled and appropriate data analyses made in addition to an explanation for missing data.

Data synthesis

A structured systematic review was performed.

Study selection and characteristics

In total, 175 potentially relevant publications were identified; 121 articles were excluded as they did not meet our inclusion criteria. A total of 54 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. Of these 54 articles included in this review, 30 were vitiligo studies and 24 were LXRs studies.

A study reported that both LXR-α and LXR-β are expressed in cultured human keratinocytes and throughout all layers of the human epidermis [7].

Important genes involved in the regulation of melanocyte functions are target genes of LXRs. It can be speculated that LXRs might be playing an important role in the pathogenesis of pigmentary disorders including vitiligo [10].

One study showed that LXR-α agonist treatment significantly induces melanocyte detachment from the basement membrane in perilesional vitiligo skin, followed by melanocyte apoptosis, suggesting its role in the pathogenesis of vitiligo [10].


  Discussion Top


This systematic review of the literature focuses on the role of LXR-α in the pathogenesis of vitiligo. Several theories were suggested to explain vitiligo pathogenesis. The main principles of all are the absence of functional melanocytes in vitiligo skin and loss of histochemically recognized melanocytes, owing to their destruction. However, the destruction is most likely a slow process resulting in a progressive decrease in melanocytes. Theories on destruction of melanocytes include autoimmune mechanisms, cytotoxic mechanisms, an intrinsic defect of melanocytes, oxidant–antioxidant mechanisms, and neural mechanisms [3]. LXRs, LXR-α and LXR-β, are members of the nuclear hormone receptors superfamily of ligand-activated transcription factors [6]. They are the key regulators of macrophage function, controlling the transcriptional program involved in lipid homeostasis and inflammation. The inducible LXR-α is highly expressed in the skin, liver, intestine, adipose tissue, macrophages, lungs, and kidney, whereas LXR-β is ubiquitously expressed [11].

Important genes involved in the regulation of melanocyte functions are target genes of LXR-α. It can be speculated that LXR-α might be playing an important role in the pathogenesis of pigmentary disorders including vitiligo [10].

Most studies on vitiligo have concentrated on the abnormality of melanocytes rather than the abnormality of keratinocytes; however, epidermal melanocytes form a functional and structural unit with neighboring keratinocytes. In fact, direct cell-to-cell contact stimulates in-vitro proliferation of melanocytes, and growth factors produced by adjacent keratinocytes regulate the proliferation and differentiation of melanocytes. The potential role of keratinocyte-derived cytokines has also been presented [5]. Keratinocytes produce several mediators, cytokines, and growth factors that support the growth and/or melanization of surrounding melanocytes. Among these molecules, endothelin-1 and stem cell factor are intrinsic/constitutive mitogens and melanogens for human melanocytes and contribute to ultraviolet B-induced pigmentation in vivo. Granulocyte–monocyte colony-stimulating factor also plays an important role in pigment cell proliferation and ultraviolet A-induced pigmentation [12]. Altered levels of keratinocyte-derived mediators have been described in vitiligo epidermis, suggesting a role of epidermal cytokines in the pathogenesis of vitiligo [13]. In addition, tumor necrosis factor-α, which has been found to be highly expressed in vitiligo skin [14], is able to induce keratinocyte apoptosis in vitro [15] and in vivo [16], and keratinocytes in vitiligo lesions have been reported to be more susceptible to apoptosis [13].

The activation of LXR-α decreases keratinocyte proliferation, increases cell death, and decreases the epidermal thickness that leads to a decrease in several keratinocyte-derived mediators and growth factors supporting the growth and/or melanization of surrounding melanocytes, suggesting the role of LXR-α in the pathogenesis of vitiligo [17]. In addition, one study found that synthetic LXR-α-specific agonists significantly inhibit cell proliferation in primary epidermal keratinocytes with subsequent affect on neighboring melanocytes and melanogenesis [8].

Another study reported that microphthalmia-associated transcription factor (MITF) is a master transcription factor for melanogenesis. Activation of LXR-α inhibits the expression of melanogenic enzymes through the acceleration of extracellular signal-regulated kinase-mediated MITF degradation, ultimately suppressing melanogenesis [18].

Many genes governed by LXR-α are related to the regulation of melanocyte functions [19]. Moreover, the expression of LXR-α was significantly upregulated in melanocytes of perilesional skin of vitiligo patients compared with the normal unaffected regions, suggesting that LXR-α might be having an important role in the pathogenesis of vitiligo [20].

Another study showed that LXR-α agonist treatment significantly induces melanocyte detachment from the basement membrane in perilesional vitiligo skin, followed by melanocyte apoptosis that shared in vitiligo pathogenesis [10].

In a study on 20 vitiligo patients in the Dermatology Department of Cairo University, it was found that LXR-α in vitiligo lesions was higher than that in controls in a highly significant manner [21].

Moreover, Chen et al. [22] reported that LXR-α mRNA and protein levels were increased in melanocytes present in the skin surrounding vitiligo lesions compared with normal skin, suggesting that LXR-α is a modulating factor in melanocytic response to this disorder.

Another study reported that fenofibrate, which belongs to the class of fibrates inhibits melanogenesis through the inhibition of enzyme activity and protein level of tyrosinase through interference with LXR signaling pathways [23].

Recently, it was found that emodin, which is an extract from polygoni multiflori ramulus, inhibits melanogenesis through the LXR-mediated pathway as emodin inhibits melanin content and tyrosinase activity concentration and time dependently. Furthermore, the expression of LXR-α gene was upregulated by emodin. Emodin regulates melanogenesis by promoting the degradation of MITF protein, which is a master transcription factor for melanogenesis [24].


  Conclusion Top


LXR-α might have a role in the pathogenesis of vitiligo through its action on genes involved in melanogenesis and also through its effect on keratinocyte death, which leads to a decrease in several keratinocyte-derived mediators and growth factors supporting the growth and/or melanization of surrounding melanocytes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Lotti TM, Berti SF, Hercogova J, Huggins RH, Lee BW, Janniger CK, et al. Vitiligo: recent insights and new therapeutic approaches. G Ital Dermatol Venerol 2012; 147:637–647.  Back to cited text no. 1
    
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Mohammed A, Rania M, Ola A, Seham R. Study of serum zinc in vitiligo. Menouf Med J 2015; 28:377–381.  Back to cited text no. 4
    
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Lee A, Kim N, Choi W, Youm Y. Less keratinocyte-derived factors related to more keratinocyte apoptosis in depigmented than normally pigmented suction blistered epidermis may cause passive melanocyte death in vitiligo. J Invest Dermatol 2005; 124:976–983.  Back to cited text no. 13
    
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Grimes EP, Morris R, Avaniss-Aghajani E, Soriano T, Meraz M, Metger A. Topical tacrolimus therapy for vitiligo: therapeutic response and skin messenger RNA expression of proinflammatory cytokines. J Am Acad Dermatol 2004; 51:52–61.  Back to cited text no. 14
    
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Meng X, Sawamura D, Baba T, Ina S, Ita K, Tamai K, et al. Transgenic TNF-α causes apoptosis in epidermal keratinocytes after subcutaneous injection of TNF-α DNA plasmid. J Invest Dermatol 1999; 113:856–858.  Back to cited text no. 16
    
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Kömüves LG, Schmuth M, Fowler AJ, Elias PM, Hanley K, Man MQ, et al. Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis. J Investig Dermatol 2002; 118:25–34.  Back to cited text no. 17
    
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Bedewi AE, Awad M, Nada E. Role of tissue liver X receptors level in skin diseases. Int J Pept Res Ther 2013; 19:275–279.  Back to cited text no. 21
    
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Kang KW, Wagley Y, Kim HW, Pokharel YR, Chung YY, Chang IY, et al. Finofibrate suppresses melanogenesis by B16-F10 melanoma cells via activation of the P38 mitogen- activated protein kinase pathway. Chem Bio Interact 2013; 205:157–164.  Back to cited text no. 23
    
24.
Kim MO, Park YS, Nho YH, Yun SK, Kim Y, Jung E, et al. Emodin isolated from polygoni multiflori ramulus inhibits melanogenesis through the liver X receptor-mediated pathway. Chem Bio Interact 2016; 250:78–84.  Back to cited text no. 24
    




 

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