title: The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells.
abstract: The flavones apigenin (4',5,7,-trihydroxyflavone) and luteolin (3',4',5,7,-tetrahydroxyflavone) are plant secondary metabolites with antioxidant, antiinflammatory, and anticancer activities. We evaluated their impact on cell signaling pathways related to insulin-resistance and type 2 diabetes. Apigenin and luteolin were identified in our U-2 OS (human osteosarcoma) cell screening assay for micronutrients triggering rapid intracellular translocation of the forkhead box transcription factor O1 (FOXO1), an important mediator of insulin signal transduction. Insulin reversed the translocation of FOXO1 as shown by live cell imaging. The impact on the expression of target genes was evaluated in HepG2 (human hepatoma) cells. The mRNA-expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pc), the lipogenic enzymes fatty-acid synthase (FASN) and acetyl-CoA-carboxylase (ACC) were down-regulated by both flavones with smaller effective dosages of apigenin than for luteolin. PKB/AKT-, PRAS40-, p70S6K-, and S6-phosphorylation was reduced by apigenin and luteolin but not that of the insulin-like growth factor receptor IGF-1R by apigenin indicating a direct inhibition of the PKB/AKT-signaling pathway distal to the IGF-1 receptor. N-acetyl-L-cysteine did not prevent FOXO1 nuclear translocation induced by apigenin and luteolin, suggesting that these flavones do not act via oxidative stress. The roles of FOXO1, FOXO3a, AKT, sirtuin1 (SIRT1), and nuclear factor (erythroid-derived2)-like2 (NRF2), investigated by siRNA knockdown, showed differential patterns of signal pathways involved and a role of NRF2 in the inhibition of gluconeogenic enzyme expression. We conclude that these flavones show an antidiabetic potential due to reduction of gluconeogenic and lipogenic capacity despite inhibition of the PKB/AKT pathway which justifies detailed investigation in vivo.
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany; Department of Endocrinology, Diabetes and Nutrition, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Bumke-Vogt
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany; Department of Endocrinology, Diabetes and Nutrition, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Osterhoff
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Borchert
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany; Department of Nutrition and Biochemistry, Sciences Faculty - Pontificia Universidad Javeriana, Bogota D.C., Colombia.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guzman-Perez
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Sarem
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Bähr
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany; Department of Endocrinology, Diabetes and Nutrition, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D047310:Apigenin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D047311:Luteolin / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D047310:Apigenin; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D019764:Phosphoenolpyruvate Carboxykinase (ATP); C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase; D047311:Luteolin