FoxO1 – the key for the pathogenesis and therapy of acne?

Abstract

Five main factors play a pivotal role in the pathogenesis of acne: androgen dependence, follicular retention hyperkeratosis, increased sebaceous lipogenesis, increased colonization with P. acnes, and inflammatory events. This paper offers a solution for the pathogenesis of acne and explains all major pathogenic factors at the genomic level by a relative deficiency of the nuclear transcription factor FoxO1. Nuclear FoxO1 suppresses androgen receptor, other important nuclear receptors and key genes of cell proliferation, lipid biosynthesis and inflammatory cytokines. Elevated growth factors during puberty and persistent growth factor signals due to Western life style stimulate the export of FoxO1 out of the nucleus into the cytoplasm via activation of the phos-phoinositide-3-kinase (PI3K)/Akt pathway. By this mechanism, genes and nuclear receptors involved in acne are derepressed leading to increased androgen receptor-mediated signal transduction, increased cell proliferation of androgen-dependent cells, induction of sebaceous lipogenesis and upregulation of Toll-like-receptor-2-dependent inflammatory cytokines. All known acne-inducing factors exert their action by reduction of nuclear FoxO1 levels. In contrast, retinoids, antibiotics and dietary intervention will increase the nuclear content of FoxO1, thereby normalizing increased transcription of genes involved in acne. Various receptor-mediated growth factor signals are integrated at the level of PI3K/Akt activation which finally results in nuclear FoxO1 deficiency.

A randomized open label comparative study to determine the various side effects and patient satisfaction of low dose continuous versus low dose intermittent oral isotretinoin therapy in moderate to severe acne vulgaris

“…Isotretinoin was earlier prescribed for cases of nodulocystic acne but is now increasingly used to treat patients of moderate to severe acne vulgaris, which are not responsive to topical therapy or oral antibiotics. 2,6 In the study muco-cutaneous dryness was most common adverse effect noted in both the groups, similar result was observed in Lee JW et al 2 study but Rao PK et al, study showed cheilitis was the most common among the side effects observed and was seen in 98% of the participants. 7 Nadia A El-Sherif et al, study showed no statistically significant differences among both groups regarding the frequency and severity of the side effects.…”

Adult Acne: Prevalence and Portrayal in Primary Healthcare Patients, in the Greater Porto Area, Portugal

“…23,24 The genes and nuclear receptors involved in acne pathogenesis are disinhibited, leading to increased androgen receptor-mediated signal transduction, increased cell proliferation of androgen-dependent cells, induction of sebaceous lipogenesis and upregulation of Toll-likereceptor-2-dependent inflammatory cytokines, leading to known acne physical features. 20,23,24 In the present study, a non-significant increase in acne prevalence was observed in subjects who drink the discussed types of milk, compared to those who do not drink milk at all; a statistically significant increase in the risk of developing acne was observed in subjects who drink semi-skimmed (reduced-fat) or whole milk, compared to subjects who do not drink milk or drink skimmed (fat-free) milk. This relationship is possibly explained by the fact that the mentioned hormones are predominantly found in the fat fraction of milk.…”

Supplementation with Lactobacillus rhamnosus SP1 normalises skin expression of genes implicated in insulin signalling and improves adult acne

“…IGF1 potently stimulates both sebaceous lipogenesis and androgen receptor signalling by promoting nuclear extrusion of the androgen receptor through the forkhead box (FOX) transcription factor O1 (FOXO1) (Agamia et al, 2016;Mirdamadi et al, 2015). A relative deficiency of the nuclear transcription factor FOXO1 is increasingly being recognized as a key player in the pathogenesis of acne (Melnik and Schmitz 2103;Melnik, 2010). Accordingly, downregulation of nuclear FOXO1 expression promotes lipogenesis, upregulation of inflammatory cytokines, and increased keratinocyte proliferation (Melnik and Schmitz 2103;Melnik, 2010).…”

“…A relative deficiency of the nuclear transcription factor FOXO1 is increasingly being recognized as a key player in the pathogenesis of acne (Melnik and Schmitz 2103;Melnik, 2010). Accordingly, downregulation of nuclear FOXO1 expression promotes lipogenesis, upregulation of inflammatory cytokines, and increased keratinocyte proliferation (Melnik and Schmitz 2103;Melnik, 2010). Conversely, retinoids commonly used to treat acne have been shown to restore physiological FOXO1 expression (Melnik and Schmitz 2013;Melnik, 2011).…”