An increase in tissue levels of LXRα mRNA was detected with the increase in disease severity: in mild acne the mean±SD was 990.37±160.67 μg/mg tissue, in moderate acne it was 1036±184.45 μg/mg tissue, and in severe acne it was 1122.33±197.7 μg/mg tissue. However, this elevation proved to be statistically insignificant (P value 0.378). In addition, the level of LXRα mRNA was insignificantly related to the course of the disease (P value 0.979), where the mean in the stationary course was 1067.25±260 μg/mg tissue, in the progressive course was 1038.45±179.8 μg/mg tissue, and in the cyclic course was 1031±163.19 μg/mg tissue. There was no correlation between the level of LXRα and age of the patients (r=−0.213, P=0.138).
Excessive sebum production from the sebaceous glands is one of the major causes of acne 8,9. Sebaceous lipogenesis resulting in accumulation of lipid droplets and subsequent sebum secretion represents a major step in the terminal differentiation of sebocytes 10. It was indicated that sebocytes, as major components of the pilosebaceous unit, may act as immune cells and may be activated by P. acnes, which recognizes altered lipid content in the sebum, followed by the production of inflammatory cytokines 11.
Strong expression of LXRα is present in the sebaceous glands, which play a critical role in sebaceous lipid production 12, as it was expressed in the skin and has been widely recognized in the regulation of genes involved in innate immunity, inflammation, and lipid biosynthesis 13. LXRα expression has been studied in sebocyte cell lineages but not in acne lesions in vivo, which was evaluated in the present study.
The current study showed that the mean level of LXRα was statistically significantly higher in lesional acne skin than in the control population. This supports the fact that increased LXR expression may have a role in acne pathogenesis. It is proposed to be through its action on inducing lipogenesis, as activation of LXRα inhibits proliferation, increases lipogenesis, and improves differentiation of sebocytes 14.
Our results agree with the findings of Russell et al.12 who demonstrated increased lipogenesis in sebocytes by synthetic stimulation of LXR; sebocytes increased significantly by 1.5-fold following incubation for 2 days with synthetic LXR agonists and increased by five-fold following incubation for 5 days when compared with untreated control cells. Furthermore, it was indicated that both LXR isotypes are expressed in the sebocytes and that LXRα stimulates lipogenesis and inhibits the proliferation of sebocytes 12.
PPAR and LXR are related to the same subfamily of nuclear receptors, and strong expression of PPARα, PPARβ/δ, PPARγ1, LXRα, and LXRβ is present in sebaceous glands 12,15. LXR ligands activate the expression of all three subtypes of PPARs and downstream target genes, indicating that PPARs may mediate the lipogenic function of LXRα in sebocytes, at least in part. It has been reported that activation of LXR involves the induction of PPARγ and downstream adipogenic gene expression in adipose tissue 16.
Our results support the findings of Elmongy and Shaker 5, who demonstrated that sebum production is the key factor in the pathophysiology of acne, and lipid mediators are able to interfere with sebocyte differentiation and sebogenesis through the activation of pathways related to PPAR. Their results showed a highly statistically significant increase in PPAR β/δ expression in acne patients compared with controls, and this expression was also significantly increased in lesional skin compared with nonlesional skin in patients; the results also showed that the increased PPAR β/δ expression could have a role in the pathogenesis of acne vulgaris through an increase in lipogenesis.
In addition to their key role in cholesterol homeostasis, LXRs have emerged as important regulators of inflammatory gene expression and innate immunity. It was shown that activation of LXR blunts the induction of classical inflammatory genes such as iNOS and COX-2 in the sebocytes 14. The expression of COX-2 and iNOS is largely stimulated by nuclear factor κB in response to a variety of inflammatory signals, suggesting that LXRα may antagonize the activation of nuclear factor κB in sebocytes 17,18. COX-2 is normally expressed in the sebocytes, and COX-2 expression is upregulated in the sebaceous glands of acne-involved skin 19,20.
It was demonstrated that LXR activators have potent anti-inflammatory activity in both the irritant and allergic contact models of cutaneous inflammation by inhibition of cytokine production upon topical treatment with LXR endogenous and synthetic agonists 21. In this study, the level of LXRα proved to be higher in inflammatory acne than in comedonal acne in a statistically significant manner. This indicates that LXRα may play a role in the progression of disease from comedonal to inflammatory, as most inflammatory acne lesions (54%) arise from comedones and 28% of lesions from normal skin 22. This is possibly through excess induction of sebaceous lipogenesis, or because LXRα alone fails to suppress inflammation. LXR activators did not reduce inflammation in LXRβ-deficient or LXRα/β-deficient mice, indicating that LXRβ was required for this anti-inflammatory effect 21. Further studies with analysis of purified primary lymphoid cultures established that activation of LXRβ by physiological or pharmacological ligands diminishes the proliferative capacity of B and T cells 23.
However, it is suggested that in sebaceous glands in-vivo LXRα alone fails to suppress inflammation. LXRβ levels were not measured in this study. It could be speculated that an unchanged or even reduced level might aid in the progression of disease from the noninflammatory phase to the inflammatory phase. Further studies on LXRβ in acne should be conducted to clarify this aspect.
In contrast, PPARs may mediate the lipogenic function of LXRα in sebocytes, at least in part 14. It was recently proven that inflammatory acne did not show a significant increase in PPAR β/δ expression compared with noninflammatory acne, although its level was significantly elevated in lesional versus nonlesional acne skin. Therefore, the increased PPAR β/δ was not simply because of inflammation and it is directly related to the pathogenesis of acne vulgaris itself 5.
Therefore, we assume that the effects of LXR on induction of acne vulgaris are not due to transrepression of inflammatory signaling pathways; rather, they are related to the control of cellular cholesterol metabolism inducing excess lipogenesis, which promotes the progression of the disease state into the papulopustular phase. It is established that LXRs regulate gene expression linked to cholesterol metabolism in a tissue-specific manner, according to whether it is in the liver, intestine, or in macrophages 24.
In addition, our results showed that the level of LXRα was significantly higher in comedonal (noninflammatory) acne in a statistically significant manner than in control biopsy samples. This result established that the increased LXRα expression is directly related to the pathogenesis of acne vulgaris itself and is not a consequence of inflammation. Hong et al.25, examined whether LXRα and its ligands regulate lipid synthesis in HaCaT cells (a transformed human keratinocyte cell lineage) depending on previous studies that demonstrated that ligands of LXRα are important in the maintenance of the normal epidermal barrier function and keratinocyte differentiation. When HaCaT cells were treated with the LXRα ligand TO901317, lipid droplets accumulated in the majority of cells, leading to lipogenesis in keratinocytes, which may enhance the epidermal barrier function of the skin. This further indicates that LXR has a role in lipid synthesis in these cells.
In our study, the level of LXRα was insignificantly correlated to disease severity, whether mild, moderate, or severe; hence, it cannot be used as a clinical marker for the disease, nor its level as a predictor for disease severity. Further, there was insignificant inverse correlation between the level of LXRα and the age of the patients. The course of the acne, whether stationary, progressive, or remitting and exacerbating (cyclic), was also insignificantly related to the level of LXRα.
Conclusion and recommendations
Excess sebum levels and inflammation, which have been implicated in initiating acne lesions, are associated with the function of LXR. LXRα could be one of the therapeutic targets for the treatment of acne, as its main role in acne pathogenesis is in increase of sebaceous lipogenesis and induction of comedogenesis, in addition to its proposed role in the progression from comedonal to inflammatory acne. Further studies are needed on the role of LXRβ in inflammatory versus noninflammatory acne lesions in vivo.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2013 Egyptian Women's Dermatologic Society
acne vulgaris; liver X receptors (LXRα); reverse transcriptase-PCR