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Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne.
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PMID:  23614736     Owner:  NLM     Status:  In-Data-Review    
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Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization.
Authors:
Bodo C Melnik; Christos C Zouboulis
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Experimental dermatology     Volume:  22     ISSN:  1600-0625     ISO Abbreviation:  Exp. Dermatol.     Publication Date:  2013 May 
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Created Date:  2013-04-25     Completed Date:  -     Revised Date:  -    
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Nlm Unique ID:  9301549     Medline TA:  Exp Dermatol     Country:  Denmark    
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Languages:  eng     Pagination:  311-5     Citation Subset:  IM    
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© 2013 John Wiley & Sons A/S.
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Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany.
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Journal Information
Journal ID (nlm-ta): Exp Dermatol
Journal ID (iso-abbrev): Exp. Dermatol
Journal ID (publisher-id): exd
ISSN: 0906-6705
ISSN: 1600-0625
Publisher: Blackwell Publishing Ltd
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© 2013 John Wiley & Sons A/S
open-access:
Accepted Day: 20 Month: 3 Year: 2013
Print publication date: Month: 5 Year: 2013
Electronic publication date: Day: 25 Month: 4 Year: 2013
Volume: 22 Issue: 5
First Page: 311 Last Page: 315
PubMed Id: 23614736
ID: 3746128
DOI: 10.1111/exd.12142

Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne
Bodo C Melnik1
Christos C Zouboulis2
1Department of Dermatology, Environmental Medicine and Health Theory, University of OsnabrückOsnabrück, Germany
2Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical CenterDessau, Germany
Correspondence: Bodo C. Melnik, MD, Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090 Osnabrück, Germany, Tel.: +49-5241-988060, Fax +49-5241-25801, e-mail melnik@t-online.de

Introduction

Acne is a disease of Western civilization with prevalence rates in adolescence of over 85% 13. Western diet (WD), characterized by high glycaemic load and high dairy protein consumption, has been suggested to be a fundamental nutritional factor promoting the acne epidemic 4,5. Proper functioning of the pathways that are involved in sensing of nutrients is central to metabolic homoeostasis 6. Notably, acne is absent in populations consuming less insulinotropic Palaeolithic diets 1,7, which exclude grains, milk and dairy products and exhibit much lower insulin/insulin-like growth factor (IGF-1) signalling (IIS) 4,7.

It is the purpose of this viewpoint to elucidate the molecular pathology of nutrient signalling of WD in the pathogenesis of acne. WD-derived metabolic signals are sensed by the forkhead box class O1 transcription factor (FoxO1) and the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1). mTORC1 is regarded as the conductor of the ‘cellular signalling symphony’ that integrates signals of cellular energy, growth factors and amino acids 8,9. Metabolic regulations mediated by FoxO1 and mTORC1 depend on upstream activation of the IIS cascade, required for adaptive nutrient homoeostasis and endocrine growth regulation 10.


Western diet upregulates insulin/IGF-1 signalling

The major endocrine changes of puberty primarily depend on hepatic secretion of IGF-1, the principal mediator of somatic growth promoting sebaceous gland (SG) cell proliferation and lipogenesis 1117. WD significantly increases insulin and IGF-1 serum levels and thus exaggerates already upregulated IIS of puberty 4,18.

Placebo-controlled studies have demonstrated that high glycaemic load diets aggravate acne, result in postprandial hyperinsulinaemia and increase serum levels of free IGF-1 1927. Epidemiological as well as clinical evidence confirmed that milk and other insulinotropic dairy products induce or aggravate acne 23,24,2834. Whey protein abuse by athletes and bodybuilders has recently been reported to induce acne flares 33,34. Milk is not a ‘simple food’ but has been identified as an endocrine growth–promoting signalling system of mammals, which activates mTORC1 signalling but inhibits FoxO1-dependent gene regulation 35 (Fig. 1).


FoxO1: a nutrient-sensing transcription factor

FoxO1 is an important transcription factor that modulates the expression of genes involved in cell cycle control, DNA damage repair, apoptosis, oxidative stress management, cell differentiation, glucose and lipid metabolism, inflammation, and innate and adaptive immune functions 3642. FoxO1 is expressed in all mammalian tissues including human SGs (Fig. 2) and plays an important role in the regulation of metabolism 43. Mouse hepatic chromatin exhibited 401 FoxO1-binding locations, regulating metabolic processing of carboxylic acids, fatty acids, steroids and retinoids 44. FoxO1 has been proposed to function as a key regulator in the pathogenesis of acne as FoxO1 senses external nutrient and internal growth factor signals and relays these to FoxO1-dependent gene regulation 45.

Central to the regulation of FoxOs is their shuttling either into the nucleus or into the cytosol. FoxO1 is inhibited by its export into the cytoplasm, which requires specific phosphorylation of FoxO1 in the nucleus by activated Akt kinase 36,37,40. The phosphoinositol-3 kinase (PI3K)/Akt cascade is stimulated by growth factors like insulin and IGF-1 and is negatively regulated by the phosphatase PTEN 46. Thus, increased IIS of WD is superimposed on enhanced IIS of puberty, the two converging in inhibition of FoxO1-dependent gene regulation 4 (Fig. 1).


FoxO1 inhibits hepatic IGF-1 secretion

Nuclear FoxO1 is highly upregulated during fasting. However, in the postprandial state and nutrient overload, enhanced IIS inhibits FoxO1 43,47,48. It is understandable that FoxO1 closely interacts with regulators of somatic growth, which is suppressed in the absence of nutrients. A major regulatory node of somatic growth and hepatic IGF-1 secretion is the growth hormone receptor (GHR).

Untreated individuals with Laron syndrome, a primary growth hormone (GH) resistance disorder due to a genetic defect of GHR, exhibit diminished congenital IGF-1 serum levels, are of short stature and never develop acne 49,50. IGF-1-deficient serum of Laron individuals increased nuclear FoxO levels and inhibited mTORC1 activity 50. The DKO mouse is an animal model mimicking Laron syndrome with impaired IIS. DKO mice have a double knockout of insulin receptor substrate-1 (IRS)-1 and IRS-2 in the liver, are shorter and exhibit 20% less body mass than control mice 10. Reduced hepatic Akt signalling with increased nuclear FoxO1 levels in DKO mice resulted in decreased expression of GHR, IGF-1 and sterol regulatory element binding protein (SREBP)-1c and increased expression of IGF-binding protein-1 (IGFBP-1) 10.

It has recently been confirmed in mice that GHR and IGFBP-1 are FoxO1 target genes 44. FoxO1-mediated inhibition of GHR expression in the liver attenuates GH-mediated synthesis and secretion of hepatic IGF-1, the main source of IGF-1 in the systemic circulation 10. Furthermore, FoxO1 induces hepatic expression of circulating IGFBP-1, thereby reducing the bioavailability of free IGF-1 10,51,52. Reduced levels of IGF-1 attenuate both general growth and SG growth and lipid synthesis 1317.

Cell growth is controlled by cell cycle inhibitors. Notably, FoxO1 activates the expression of the cell cycle inhibitors p21 and p27 (see Data S1) 5358. Moreover, FoxO1 activates the expression of the eukaryotic initiation factor 4E-binding protein-1 (4E-BP-1), which is a major substrate of mTORC1 and functions as a potent translational inhibitor and growth suppressor (Table 1) 59,60.


FoxO1 inhibits lipogenesis

FoxO1 not only suppresses protein synthesis and cell growth, but also lipid metabolism. FoxO1 regulates the key transcription factor of lipid synthesis SREBP-1c (Table 1) 10,61. IGF-1 induced SREBP-1 expression and enhanced lipogenesis in SEB-1 sebocytes via activation of the PI3K/Akt pathway 17, whereas FoxO1 antagonized the expression of SREBP-1c 10,61. Thus, reduced expression of SREBP-1 should be expected from a low glycaemic load diet associated with attenuated IIS 4. In fact, Kwon et al. 25 demonstrated that a 10-week low glycaemic load diet reduced SREBP-1 expression in the skin of acne patients, reduced the size of SGs, mitigated cutaneous inflammation and improved acne. Furthermore, FoxO1 suppresses the activity of peroxisome proliferator–activated receptor-γ (PPARγ) and LXRα 6164 that both costimulate SG lipogenesis (Table 2) 6570.

Isotretinoin's sebum-suppressive effect has recently been associated with upregulated FoxO1 expression 71. Reported reductions in IGF-1 serum levels during isotretinoin treatment 72 are thus well explained by FoxO1-mediated inhibition of hepatic GHR expression resulting in diminished hepatic synthesis of IGF-1.


FoxO1 suppresses androgen signalling

Sebaceous gland growth and acne are androgen dependent 73. The growth of androgen-responsive tissues is coordinated with general somatic growth 74. IGF-1 stimulates gonadal and adrenal androgen synthesis as well as intracutaneous intracrine conversion of testosterone to tenfold more active dihydrotestosterone, the most potent androgen receptor (AR) ligand 11 (Fig. 1). Enhanced hepatic IGF-1 synthesis by WD may thus increase the availability of potent androgens in the skin.

Remarkably, only a few acne patients exhibit hyperandrogenaemia, a fact that points to the predominance of peripheral tissue-dependent androgen/AR sensitivity for the manifestation of acne 73. Intriguingly, FoxO1 functions as an AR cosuppressor 7577. Nuclear extrusion of FoxO1 by high IIS relieves FoxO1-mediated repression of AR transactivation. Thus, insulinotropic WD may stimulate AR-mediated signalling, which explains enhanced peripheral androgen responsiveness (Fig. 1).

Both AR and IIS synergistically increase SREBP-1-mediated lipogenesis and upregulate lipogenic pathways 78. Whereas FoxO1 stimulates p21 and p27 expression (see Data S1), AR signalling rapidly reduces p27 by increasing its proteasome-mediated degradation 79. These findings exemplify the nutrient-dependent crosstalk between AR and IIS.


FoxO1 reduces oxidative stress

Overnutrition and anabolic states with enhanced mTORC1 activity are associated with increased oxidative stress, which has been observed in acne vulgaris 8083. FoxOs upregulate defense mechanisms against reactive oxygen species (ROS). FoxO1 induces the expression of haeme oxygenase 1 and thereby reduces mitochondrial ROS formation 43,84. FoxO1 and FoxO3 mediate the expression of the ROS scavenger sestrin3 (Fig. 1). FoxO3 stimulates the expression of ROS-degrading enzymes manganese superoxide dismutase and catalase 8587. Hence, FoxOs are key players of redox signalling and link WD to enhanced metabolic oxidative stress in acne vulgaris 81,82,87.


FoxO1 links nutritional status to innate and adaptive immunity

FoxO family members suppress the highly substrate- and energy-dependent process of T-cell activation 38, whereas FoxO1 deficiency in vivo resulted in spontaneous T-cell activation and effector differentiation 39. Increased CD4+ T-cell infiltration and enhanced IL-1 activity have been detected in acne-prone skin areas prior to comedo formation 88. Thus, FoxO1 links nutrient availability and metabolic conditions to T-cell homoeostasis 89,90 (see Data S1).


FoxOs control antimicrobial peptide synthesis

In Drosophila flies, dFOXO controls the expression of several antimicrobial peptides (AMPs) in the skin 91. AMP induction is lost in dFOXO null mutants but enhanced when dFOXO is overexpressed. In Drosophila, AMP activation can be achieved independently of pathogen-dependent pathways, indicating direct cross-regulation between metabolism and innate immunity 91. As in Drosophila, downregulated FoxO inhibited AMP expression in the polyp Hydra vulgaris92.

Downregulated FoxO signalling by WD may thus favour an AMP-deficient follicular microenvironment, which may allow overgrowth of P. acnes. WD would not only overstimulate sebum production favouring P. acnes growth but may diminish AMP-controlled host responses against P. acnes, which may ultimately stimulate inflammatory TLR-mediated innate immune responses against hypercolonized P. acnes93,94. Upregulated TLR-driven innate immune responses against P. acnes with overexpression of TNF-α may further enhance SG lipogenesis via activated proinflammatory IKKβ-TSC1-mTORC1 signalling (see Data S1, Fig. S1) 95.


mTORC1: Convergence point of nutrient signalling in acne

mTORC1 is an evolutionarily conserved nutrient-sensing kinase that regulates growth and metabolism in all eukaryotic cells 8,9,83. mTORC1 signalling serves as a ‘growth checkpoint’ surveying the status of the extra- and intracellular milieu of growth factors and nutrients 83,96. mTORC1 signalling stimulates gene transcription, translation, ribosome biogenesis, protein synthesis, cell growth, cell proliferation and lipid synthesis but suppresses autophagy 8,97101. In mammalian cells, two functionally different mTOR complexes exist: mTORC1 and mTORC2. mTORC1 contains the partner protein Raptor that interacts with mTORC1 substrates for their phosphorylation. mTORC2 contains the protein Rictor and activates the kinase Akt. mTORC1 controls the G1/S transition and G2/M progression of the cell cycle 98. The mTORC1 signalling network senses and relays diverse inputs of nutrients, growth factors and cellular energy to a central ‘signalling core’ that consists of Akt, TSC1/TSC2, Rheb and mTORC1 itself (Fig. 1) 82,102. Liver kinase B1 and the energy sensor AMP-activated protein kinase (AMPK) are critical regulators of mTORC1 103 (see mTORC1 nutrisome signalling, Data S1).

Western diet overactivates mTORC1 by providing an abundance of dairy- and meat-derived essential amino acids, increased IIS induced by dairy protein consumption and high glycaemic load and suppressed AMPK activity by calorie excess. As protein and lipid biosynthesis, cell growth and proliferation are coordinated by mTORC1, it is obvious that mTORC1 plays a key role in acne pathogenesis, characterized by increased proliferation of acroinfundibular keratinocytes, SG hyperplasia and increased SG lipogenesis 5.


Acne and mTORC1-driven insulin resistance

Nutrient signalling of WD results in increased activation of downstream substrates of mTORC1, the S6 kinases S6K1 and S6K2. S6K1-mediated phosphorylation of insulin receptor substrate 1 (IRS-1) downregulates IIS and thus induces insulin resistance. Dietary fatty acids directly activate S6K1 independent of mTORC1 104. Insulin resistance is considered to be a physiological feature of increased growth during puberty 105. However, pathologically persistent insulin resistance is associated with the metabolic syndrome as well as acne-associated syndromes 106,107. Thus, increased mTORC1/S6K1 signalling explains the reported associations between WD, acne, increased body mass index (BMI) and insulin resistance 32,108,109.


mTORC1 regulates lipid synthesis

Increased SG lipid biosynthesis is responsible for seborrhoea and SG hyperplasia. Importantly, the key transcription factor of lipid biosynthesis SREBP-1 depends on mTORC1 activation 110. mTORC1 phosphorylates lipin-1, which controls the access of SREBP-1 to the promoter region of SREBP-1-dependent lipogenic genes in the nucleus 110.


FoxO1: the rheostat regulating mTORC1

As both mTORC1 and FoxO1 integrate nutrient and growth factor signals, it is conceivable that they interact with each other to coordinate cellular responses to nutrient availability. FoxOs are pivotal inhibitors of mTORC1 and have emerged as important rheostats that modulate the activity of Akt and mTORC1 111. FoxO1, FoxO3 and FoxO4 induce the expression of sestrin3 that activates AMPK, which inhibits mTORC1 (Fig. 1) 85. Activated AMPK phosphorylates FoxO3 and facilitates its nuclear localization 112. Furthermore, Akt-phosphorylated cytoplasmic FoxO1 binds to TSC2 and thereby dissociates the TSC1/TSC2 complex, which activates mTORC1 113. Thus, activated Akt inhibits FoxO1, FoxO3 and FoxO4 through direct phosphorylation and indirectly activates mTORC1, which in turn increases protein and lipid synthesis and induces insulin resistance 113.

mTORC1-activated S6K1 via inhibitory IRS-1-phosphorylation elicits a negative feedback loop to inhibit Akt. In contrast, FoxO1 also induces insulin and IGF-1 receptors and IRS-2, a feedback mechanism, which increases insulin sensitivity 111,114. FoxO1 elevates the expression of Rictor, leading to increased mTORC2 activity that consecutively activates Akt.

Taken together, FoxOs maintain homoeostatic balance between Akt, mTORC1 and mTORC2 (Table 3) 85,111. FoxO1 raises the expression of 4E-BP1, a potent repressor of mRNA translation and suppressor of cell growth 59,60. FoxO1 suppresses the expression of the pseudokinase tribbles 3, which inhibits Akt activity 115,116. FoxO3 elevates the expression of the autophagy-related gene Bnip3 that inhibits mTORC1 117,118. FoxO3 induces the expression of TSC1 and thereby inhibits mTORC1 (Table 1) 119.

In summary, FoxO transcription factors, especially FoxO1, inhibit the activity of mTORC1 at multiple levels of cellular regulation (Table 3).


Conclusion

Insulinotropic WD impairs FoxO1-mediated gene regulation in acne 45. FoxO1 controls the somatotropic axis, modifies the magnitude of AR signalling, interacts with important nuclear regulators of SG homoeostasis, metabolism and lipogenesis and most importantly coordinates the activity of mTORC1.

Acne vulgaris with exacerbated pilosebaceous mTORC1 signalling belongs to the family of mTORC1-driven diseases of civilization 5. Dermatologists counselling acne patients, especially the young, should not only focus on the treatment of skin pathology but should advise on means to correct inappropriate systemic mTORC1 signalling that is aggravated by WD. This is essential to prevent more serious mTORC1-driven diseases of civilization like obesity, diabetes and cancer 5,120.

Nutritional therapy of acne should (i) normalize total calorie intake, (ii) lower glycaemic load and (iii) restrict total dairy protein consumption, especially whey protein abuse 5,19,25,3234. The ideal nutritional therapy of acne should favour (i) a Palaeolithic-type diet containing less insulinotropic grains and minimal or no dairy products to avoid increased IIS and androgen precursors present in dairy products, (ii) higher consumption of vegetables, fruits and green tea containing natural plant-derived mTORC1 inhibitors (epigallocatechin gallate, resveratrol and other natural polyphenols) 121 and (iii) increased consumption of fish (lower insulinaemic index than dairy protein; source of anti-inflammatory ω-3 fatty acids) and adequate intake of vitamin D (see Data S1, Fig. S1).

Deeper insights into the regulation of nutrient signalling may help dermatologists to understand the central role of WD in the pathogenesis and treatment of acne and may shed a new light on the precious experience of Hippocrates of Kos who stated about 2400 years ago: ‘Your diet should be your medicine, and your medicine should be your diet’.


Conflict of interests

The authors have declared no conflict of interest.


References
1. Cordain L,Lindeberg S,Hurtado M,et al. Arch DermatolYear: 2002381584159012472346
2. Collier CN,Harper JC,Cafardi JA,et al. J Am Acad DermatolYear: 200858565917945383
3. Ghodsi SZ,Orawa H,Zouboulis CC. J Invest DermatolYear: 20091292136214119282841
4. Melnik BC,John SM,Schmitz G. Nutr Metab (Lond)Year: 201184121699736
5. Melnik B. DermatoendocrinolYear: 20124203222870349
6. Hotamisligil GS,Erbay E. Nat Rev ImmunolYear: 2008892393419029988
7. Lindeberg S,Eliasson M,Lindahl B,et al. MetabolismYear: 1999481216121910535381
8. Foster KG,Fingar DC. J Biol ChemYear: 2010285140711407720231296
9. Inoki K,Ouyang H,Li Y,et al. Microbiol Mol Biol RevYear: 2005697910015755954
10. Dong XC,Copps KD,Guo S,et al. Cell MetabYear: 20088657618590693
11. Melnik BC,Schmitz G. Exp DermatolYear: 20091883384119709092
12. Cara JF,Rosenfield RL,Furlanetto RW. Am J Dis ChildYear: 19871415625643578171
13. Deplewski D,Rosenfield RL. Endocr RevYear: 20002136339210950157
14. Deplewski D,Rosenfield RL. EndocrinologyYear: 19991404089409410465280
15. Cappel M,Mauger D,Thiboutot D. Arch DermatolYear: 200514133333815781674
16. Vora S,Ovhal A,Jerajani H,et al. Br J DermatolYear: 200815997999518647304
17. Smith TM,Gilliland K,Clawson GA,et al. J Invest DermatolYear: 20081281286129317989724
18. Cordain L,Eades MR,Eades MD. Comp Biochem Physiol A Mol Integr PhysiolYear: 20031369511214527633
19. Smith RN,Mann NJ,Braue A,et al. Am J Clin NutrYear: 20078610711517616769
20. Smith RN,Braue A,Varigos GA,et al. J Dermatol SciYear: 200850415218178063
21. Smith RN,Mann NJ,Braue A,et al. J Am Acad DermatolYear: 20075724725617448569
22. Smith R,Mann NJ,Mäkeläinen H,et al. Mol Nutr Food ResYear: 20085271872618496812
23. Jung JY,Yoon MY,Min SU,et al. Eur J DermatolYear: 20102076877220822969
24. Ismail NH,Abdul Manaf Z,Azizan NZ. BMC DermatolYear: 2012121322898209
25. Kwon HH,Yoon JY,Hong JS,et al. Acta Derm VenereolYear: 20129224124622678562
26. Skroza N,Tolino E,Semyonov L,et al. Scand J Public HealthYear: 20124046647422833557
27. Paoli A,Grimaldi K,Toniolo L,et al. Skin Pharmacol PhysiolYear: 20122511111722327146
28. Melnik B. J Dtsch Dermatol GesYear: 2009736437019243483
29. Adebamowo CA,Spiegelman D,Danby FW,et al. J Am Acad DermatolYear: 20055220721115692464
30. Adebamowo CA,Spiegelman D,Berkey CS,et al. Dermatol Online JYear: 20061211217083856
31. Adebamowo CA,Spiegelman D,Berkey CS,et al. J Am Acad DermatolYear: 20085878779318194824
32. Di Landro A,Cazzaniga S,Parazzini F,et al. J Am Acad DermatolYear: 2012671129113522386050
33. Silverberg NB. CutisYear: 201290707222988649
34. Simonart T. DermatologyYear: 201222525625823257731
35. Melnik BC,John SM,Carrera-Bastos P,et al. Nutr Metab (Lond)Year: 201297422891897
36. Huang H,Tindall DJ. J Cell SciYear: 20071202479248717646672
37. Van der Heide LP,Hoekman MF,Smid MP. Biochem JYear: 200438029730915005655
38. Peng SL. Int J Biochem Cell BiolYear: 20094248248519850149
39. Ouyang W,Beckett O,Flavell RA,et al. ImmunityYear: 20093035837119285438
40. Essaghir A,Dif N,Marbehant CY,et al. J Biol ChemYear: 2009284103341034219244250
41. Maiese K,Chong ZZ,Shang YC,et al. Cell CycleYear: 200873829383919066462
42. Nakae J,Oki M,Cao Y. FEBS LettYear: 2008582546718022395
43. Cheng Z,White MF. Antioxid Redox SignalYear: 20111464966120615072
44. Shin DJ,Joshi P,Hong SH,et al. Nucleic Acids ResYear: 201240114991150923066095
45. Melnik BC. J Dtsch Dermatol GesYear: 2010810511420151947
46. Chalhoub N,Baker S. Annu Rev PatholYear: 2009412715018767981
47. Gross DN,Wan M,Birnbaum MJ. Curr Diab RepYear: 2009920821419490822
48. Cheng Z,Guo S,Copps K,et al. Nat MedYear: 2009151307131119838201
49. Ben-Amitai D,Laron Z. J Eur Acad Dermatol VenereolYear: 20112595095421054577
50. Guevara-Aguirre J,Balasubramanian P,Guevara-Aguirre M,et al. Sci Transl MedYear: 2011319
51. Tomizawa M,Kumar A,Perrot V,et al. J Biol ChemYear: 20002757289729510702299
52. Gan L,Han Y,Bastianetto S,et al. Biochem Biophys Res CommunYear: 20053371092109616236254
53. van der Vos KE,Coffer PJ. Antioxid Redox SignalYear: 20111457959220673124
54. Nakae J,Kitamura T,Kitamura Y,et al. Dev CellYear: 2003411912912530968
55. Seoane J,Le HV,Shen L,et al. CellYear: 200411721122315084259
56. Dijkers PF,Medema RH,Pals C,et al. Mol Cell BiolYear: 2000209138914811094066
57. Medema RH,Kops GJ,Bos JL,et al. NatureYear: 200040478278710783894
58. Stahl M,Dijkers PF,Kops GJ,et al. J ImmunolYear: 20021685024503111994454
59. Jünger MA,Rintelen F,Stocker H,et al. J BiolYear: 200322012908874
60. Puig O,Marr MT,Ruhf ML,et al. Genes DevYear: 2003172006202012893776
61. Kamei Y,Miura S,Suganami T,et al. EndocrinologyYear: 20081492293230518202130
62. Armoni M,Harel C,Karni S,et al. J Biol ChemYear: 2006281198811989116670091
63. Dowell P,Otto TC,Adi S,et al. J Biol ChemYear: 2003278454854549112966085
64. Fan WQ,Imamura T,Sonoda N,et al. J Biol ChemYear: 2009284121881219719246449
65. Chen W,Yang CC,Sheu HM,et al. J Invest DermatolYear: 200312144144712925198
66. Makrantonaki E,Zouboulis CC. Br J DermatolYear: 200715642843217300229
67. Zouboulis CC,Saborowski A,Boschnakow A. DermatologyYear: 2005210363815604543
68. Zhang Q,Seltmann H,Zouboulis CC,et al. J Invest DermatolYear: 2006126424816417216
69. Trivedi NR,Cong Z,Nelson AM,et al. J Invest DermatolYear: 20061262002200916675962
70. Hong I,Lee MH,Na TY,et al. J Invest DermatolYear: 20081281266127217960176
71. Melnik BC. DermatoendocrinolYear: 2011314116522110774
72. Karadag AS,Ertugrul DT,Tutal E,et al. Br J DermatolYear: 201016279880220128787
73. Makrantonaki E,Ganceviciene R,Zouboulis C. DermatoendocrinolYear: 2011314114922110774
74. Li J,Al-Azzawi F. MaturitasYear: 20096314214819372015
75. Heemers HV,Tindall DJ. Endocr RevYear: 20072877880817940184
76. Yanase T,Fan W. Vitam HormYear: 200980651666
77. Ma Q,Fu W,Li P,et al. Mol EndocrinolYear: 20092321322519074551
78. Heemers HV,Verhoeven G,Swinnen JV. Mol EndocrinolYear: 2006202265227716455816
79. Fang Z,Zhang T,Dizzeyi N,et al. J Biol ChemYear: 20122872090209822139837
80. James AM,Collins Y,Logan A,et al. Trends Endocrinol MetabYear: 20122342943422831852
81. Arican O,Kurutas EB,Sasmaz S. Mediators InflammYear: 2005638038416489259
82. Bowe WP,Patel N,Logan AC. J Drugs DermatolYear: 20121174274622648222
83. Kapahi P,Chen D,Rogers AN,et al. Cell MetabYear: 20101145346520519118
84. Cheng Z,White MF. Cell CycleYear: 2010921922020023377
85. Chen CC,Jeon SM,Bhaskar PT,et al. Dev CellYear: 20101859260420412774
86. Nogueira V,Park Y,Chen CC,et al. Cancer CellYear: 20081445847019061837
87. Dansen TB. Antioxid Redox SignalYear: 20111455956121083421
88. Jeremy AH,Holland DB,Roberts SG,et al. J Invest DermatolYear: 2003121202712839559
89. Dejean AS,Hedrick SM,Kerdiles YM. Antioxid Redox SignalYear: 20111466367420673126
90. Kerdiles YM,Beisner DR,Tinoco R,et al. Nat ImmunolYear: 20091017618419136962
91. Becker T,Loch G,Beyer M,et al. NatureYear: 201046336937320090753
92. Boehm AM,Khalturin K,Anton-Erxleben F,et al. Proc Natl Acad Sci USAYear: 2012109196971970223150562
93. Melnik BC. G Ital Dermatol VenereolYear: 201014555957120930691
94. Jahns AC,Lundskog B,Gancevicience R,et al. Br J DermatolYear: 2012167505822356121
95. Choi JJ,Park MY,Lee HJ,et al. J Dermatol SciYear: 20126517918822305016
96. Shaw RJ,Cantley LC. NatureYear: 200644142443016724053
97. Bhaskar PT,Hay N. Dev CellYear: 20071248750217419990
98. Wang X,Proud CG. CellYear: 200919260267
99. Sengupta S,Peterson TR,Sabatini DM. Mol CellYear: 20104031032220965424
100. Suzuki T,Inoki K. Acta Biochim Biophys SinYear: 20114367167921785113
101. Wang X,Proud CG. J Mol Cell BiolYear: 2011320622021138990
102. Avruch J,Long X,Ortiz-Vega S,et al. Am J Physiol Endocrinol MetabYear: 2009296592602
103. Shaw RJ. Acta Physiol (Oxf)Year: 2009196658019245654
104. Castaneda T,Abplanalp W,Um SH,et al. PLoS ONEYear: 20127e3263122412899
105. Guerico G,Rivarola MA,Chaler E,et al. J Clin Endocrinol MetabYear: 2003881389139312629134
106. Zick Y. Sci STKEYear: 20052005pe415671481
107. Chen W,Obermayer-Pietsch B,Hong JB,et al. J Eur Acad Dermatol VenereolYear: 20112563764621198949
108. Tsai MC,Chen WC,Cheng YW,et al. Eur J DermatolYear: 20061625125316709487
109. Del Prete M,Mauriello MC,Faggiano A,et al. EndocrineYear: 20124255556022447309
110. Porstmann T,Santos CR,Lewis C,et al. Biochem Soc TransYear: 20093727828319143646
111. Hay N. Biochim Biophys ActaYear: 201118131965197021440577
112. Greer EL,Oskoui PR,Banko MR,et al. J Biol ChemYear: 2007282301073011917711846
113. Cao Y,Kamioka Y,Yokoi N,et al. J Biol ChemYear: 200652402424025117077083
114. Marr MT 2nd,D′Alessio JA,Puig O,et al. Genes DevYear: 20072117518317234883
115. Matsumoto M,Han S,Kitamura T,et al. J Clin InvestYear: 20061162464247216906224
116. Du K,Herzig S,Kulkarni RN,et al. ScienceYear: 20033001574157712791994
117. Mammucari C,Milan G,Romanello V,et al. Cell MetabYear: 2007645847118054315
118. Li Y,Wang Y,Kim E,et al. J Biol ChemYear: 2007282358033581317928295
119. Khatri S,Yepiskoposyan H,Gallo CA,et al. J Biol ChemYear: 2010285159601596520371605
120. Zoncu R,Efeyan A,Sabatini DM. Nat Rev Mol Cell BiolYear: 201112213521157483
121. Landete JM. Crit Rev Food Sci NutrYear: 20125293694822747081
Supporting Information

Additional Supporting Information may be found in the online version of this article:

Data S1. Further FoxO1/mTORC1 interactions.

Figure S1. Interaction of acne risk-enhancing gene polymorphisms on FoxO1-/mTORC1 mediated nutrient signalling of Western diet.

Click here for additional data file (exd0022-0311-SD1.doc)

Click here for additional data file (exd0022-0311-SD2.ppt)


Figures

[Figure ID: fig01]
Figure 1 

Increased insulin/IGF-1 signalling (IIS) of Western diet (WD) results in Akt-mediated FoxO1 inhibition by nuclear extrusion. Akt-mediated phosphorylation of TSC2 attenuates the inhibitory effect of TSC1/TSC2 on Rheb, thus promotes mTORC1 activation. In contrast, nuclear activation of FoxO1 stimulates the expression of sestrin3, which via AMPK activation inhibits mTORC1. Increased IIS of WD is superimposed on enhanced IIS of puberty, thereby promotes the development of acne. FoxO1 inhibits GHR expression, hepatic IGF-1 synthesis and androgen receptor (AR) transactivation. GIP, glucose-dependent insulinotropic polypeptide; GH, growth hormone; GHR, GH receptor; Leu, leucine; LAT, L-type amino acid transporter; IR, insulin receptor; IRS, insulin receptor substrate; PI3K, phosphoinositol-3 kinase; Akt, Akt kinase (protein kinase B); FoxO, forkhead box transcription factor class O; TSC, tuberous sclerosis complex; Rheb, ras-homolog enriched in brain; mTORC1, mammalian target of rapamycin complex 1; AMPK, AMP kinase; T, testosterone; DHT, dihydrotestosterone.



[Figure ID: fig02]
Figure 2 

Immunohistochemical detection of FoxO1 in human sebaceous glands (kindly provided by Dr. A. I. Liakou, Dessau Medical Center, Germany)



Tables
[TableWrap ID: tbl1] Table 1 

Important FoxO1-regulated target genes in the pathogenesis of acne


Growth hormone receptor (GHR) Suppression of GHR expression with downregulation of hepatic IGF-1 synthesis
IGF-binding protein-1 (IGFBP-1) Upregulation of IGFBP-1 expression, reduction in circulating free IGF-1
Eukaryotic initiation factor 4 binding protein-1 (4E-BP-1) Activation of 4E-BP-1 expression inhibiting mRNA translation
p21 Activation of p21 expression, cell cycle inhibition, growth inhibition
p27 Activation of p27, cell cycle inhibition, growth inhibition
Sestrin3 Activation of sestrin3 expression, activation of AMPK-mediated phosphorylation of TSC2 activating the inhibitory function of TSC1/TSC2, thus suppressing mTORC1
Haeme oxygenase-1 (OH-1) Activation of OH-1 expression, inhibition of mitochondrial function and reactive oxygen species formation, inhibition of NFκB, inhibition of inflammation

[TableWrap ID: tbl2] Table 2 

FoxO1 interaction with regulatory proteins and transcription factors


Androgen receptor (AR) Suppression of AR transactivation
PPARγ Suppression of PPARγ and PPARγ-mediated lipogenesis
LXRα Suppression of RXR/LXRα-mediated activation of SREBP-1
TSC2 Akt-phosphorylated cytoplasmic FoxO1 dissociates and thereby inhibits the TSC1/TSC2 heterodimer
β-Catenin Augmentation of nuclear FoxO1 signalling
GSK3 Modulation of GSK3-TSC2-mTORC1 signalling
CRM1 Nuclear FoxO1 export

[TableWrap ID: tbl3] Table 3 

Impact of FoxOs in the regulation of mTORC1 activity


nFoxO1↑ GHR↓, hepatic IGF-1↓, Akt↓ mTORC1↓
nFoxO1↑ IGFBP-1↑, free IGF-1↓, Akt↓ mTORC1↓
nFoxO1↑, nFoxO3↑, nFoxO4↑ Sestrin3↑, AMPK↑, TSC2↑ mTORC1↓
nFoxO1↑ AR↓, mTORC2↓, Akt↓ AR↓, LAT↓, Regulator↓ mTORC1↓
nFoxO1↑ 4E-BP-1↑ mTORC1↓
nFoxO1↑ Rictor↑, mTORC2 assembly↑ mTORC1↓
nFoxO1↑ Trb3↑, Akt↓ mTORC1↓
nFoxO3↑ Bnip3↑, Rheb↓ mTORC1↓
nFoxO3↑ FoxO1↑ TSC1↑ mTORC1↓
cFoxO1↑ TSC1/TSC2↓, Rheb↑ mTORC1↑

nFoxO, nuclear FoxO; cFoxO, cytoplasmic FoxO; LAT, L-type amino acid transporter.



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Keywords: acne, FoxO1, mTORC1, nutrient signalling, Western diet.

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