Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne (original) (raw)
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Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet
Dermato-endocrinology, 2012
The purpose of this paper is to highlight the endocrine signaling of Western diet, a fundamental environmental factor involved in the pathogenesis of epidemic acne. Western nutrition is characterized by high calorie uptake, high glycemic load, high fat and meat intake, as well as increased consumption of insulin- and IGF-1-level elevating dairy proteins. Metabolic signals of Western diet are sensed by the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), which integrates signals of cellular energy, growth factors (insulin, IGF-1) and protein-derived signals, predominantly leucine, provided in high amounts by milk proteins and meat. mTORC1 activates SREBP, the master transcription factor of lipogenesis. Leucine stimulates mTORC1-SREBP signaling and leucine is directly converted by sebocytes into fatty acids and sterols for sebaceous lipid synthesis. Over-activated mTORC1 increases androgen hormone secretion and most likely amplifies androgen-driven mTORC1 s...
FoxO1 - the key for the pathogenesis and therapy of acne?
JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 2010
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 phosphoinositide-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-likereceptor-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 Figure 1: Regulatory functions of nuclear transcription factor FoxO1. FoxO1 directly inhibits nuclear receptors like PPAR␥ or LXR. FoxO1 activates or represses the promoter of target genes.
Experimental Dermatology, 2013
Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxiatelangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFa signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKb-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents.
Maedica, 2018
Nutrition and food are one of the most complex aspects of human lives, being influenced by biochemical, psychological, social and cultural factors. The Western diet is the prototype of modern dietary pattern and is mainly characterized by the intake of large amounts of red meat, dairy products, refined grains and sugar. Large amounts of scientific evidence positively correlate Western diet to acne, obesity, diabetes, heart disease and cancer, the so-called "diseases of civilization". The pathophysiological common ground of all these pathologies is the IGF-1 and mTORC pathways, which will be disscussed further in this paper.
Linking diet to acne metabolomics, inflammation, and comedogenesis: an update
Clinical, Cosmetic and Investigational Dermatology, 2015
Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1) hyperglycemic carbohydrates, 2) milk and dairy products, 3) saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs). Diet-induced insulin/insulin-like growth factor (IGF-1)-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs), glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1). Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c), crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA-and ∆6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea) and composition (dysseborrhea) promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a "danger signal," stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte proliferation. Oleate stimulates P. acnes adhesion, keratinocyte proliferation, and comedogenesis via interleukin-1α release. Thus, diet-induced metabolomic alterations promote the visible sebofollicular inflammasomopathy acne vulgaris. Nutrition therapy of acne has to increase FoxO1 and to attenuate mTORC1/SREBP-1c signaling. Patients should balance total calorie uptake and restrict refined carbohydrates, milk, dairy protein supplements, saturated fats, and trans-fats. A paleolithic-like diet enriched in vegetables and fish is recommended. Plantderived mTORC1 inhibitors and ω-3-PUFAs are promising dietary supplements supporting nutrition therapy of acne vulgaris.
Experimental Dermatology, 2009
It is the purpose of this viewpoint article to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne. The key regulator IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne. In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5a-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. Milk consumption results in a significant increase in insulin and IGF-1 serum levels comparable with high glycaemic food. Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signalling pathways of insulin receptors, IGF-1 receptor and fibroblast growth factor receptor-2b. Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin ⁄ IGF1-signalling. Metformin treatment, and diets low in milk protein content and glycaemic index reduce increased IGF-1 signalling. Persistent acne in adulthood with high IGF-1 levels may be considered as an indicator for increased risk of cancer, which may require appropriate dietary intervention as well as treatment with insulin-sensitizing agents.
Plewig and Kligman´s Acne and Rosacea, 2019
Acne and Nutrition Core Messages • High glycemic carbohydrates and milk are major factors of Western diet that can induce or aggravate acne vulgaris. • Milk can be considered as an endocrine signaling system and enhances IGF-1 serum levels and mTORC1 activity promoting growth and anabolism. • Enhanced mTORC1/S6K1 signaling by Western diet is proposed to explain the association of acne vulgaris with increased body mass index and insulin resistance. • Some studies showed high glycemic load diets can enhance insulin/IGF-1/mTORC1/SREBP1-mediated production of sebum, whereas strict caloric restriction can curtail sebum secretion. • Evidence suggests dietary intervention may readjust deviated p53/mTORC1 signaling. • Large well-controlled studies are required to provide evidence-based recommendations for dietary intervention in acne.
Acne and diet: a review of pathogenic mechanisms
Boletín Médico del Hospital Infantil de México
Acne is a chronic inflammatory disease of the pilosebaceous unit with multifactorial etiology. Abnormal proliferation of keratinocytes, altered sebum production, inflammation of the sebaceous follicle, and colonization by Cutibacterium acnes have been traditionally implicated. However, the diet has also been highlighted in the pathogenesis because of its direct relation with some biochemical markers and the transcription of specific genes associated with sebaceous gland activity, inflammation, and bacterial proliferation, which together promote the development of the disease, affect the severity of the condition, and modify its response to treatment.