title: Insulin and insulin-like growth factor-1 can modulate the phosphoinositide-3-kinase/Akt/FoxO1 pathway in SZ95 sebocytes in vitro.
abstract: A recent hypothesis suggests that a high glycaemic load diet-associated increase of insulin-like growth factor-1 (IGF-1) and insulin may promote acne by reducing nuclear localization of the forkhead box-O1 (FoxO1) transcription factor via activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. Using SZ95 sebocytes as a model, we investigated the effect of the most important insulinotropic western dietary factors, IGF-1 and insulin on acne. SZ95 sebocytes were stimulated with different concentrations of IGF-1 and insulin (0.001, 0.01, 0.1 and 1 μM) for 15 to 120 min ± PI3K inhibitor LY294002 (50 μM). Cytoplasmic and nuclear protein expression of p-Akt and p-FoxO1 as well as FoxO transcriptional activity was analysed. In addition, the proliferation and differentiation of sebocytes and their TLR2/4 expression were determined. We found that high concentrations of IGF-1 and insulin differentially stimulate the PI3K/Akt/FoxO1 pathway by an early up-regulation of cytoplasmic p-Akt and delayed up-regulation of p-FoxO1 resulting in FoxO1 shift to the cytoplasm and the reduction of FoxO transcriptional activity, physiological serum concentration had no effect. IGF-1 at concentrations of 0.1 and 1 μM significantly reduced proliferation but increased differentiation of sebocytes to a greater extent than insulin (0.1 and 1 μM), but up-regulated TLR2/4 expression to comparable extent. These data provide the first in vitro evidence that FoxO1 principally might be involved in the regulation of growth-factor-stimulatory effects on sebaceous lipogenesis and inflammation in the pathological condition of acne. However, the in vivo significance under physiological conditions remains to be elucidated.
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Mirdamadi
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Thielitz
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Wiede
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Goihl
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Papakonstantinou
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Simeoni
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Bommhardt
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Quist
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany. Electronic address: harald.gollnick@med.ovgu.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Gollnick
mesh_terms: D000152:Acne Vulgaris / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D050155:Lipogenesis; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Acne; FoxO1; High glycaemic load diet; IGF-1; Insulin; Sebocytes