title: Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells.
abstract: Ad4-binding protein/steroidogenic factor 1 (Ad4BP/SF-1), a member of the nuclear receptor superfamily, is expressed in steroidogenic cells and regulates all steroidogenic gene expression. We recently employed mRNA and chromatin immunoprecipitation sequence (ChIP-seq) to demonstrate that Ad4BP/SF-1 directly regulates the expression of nearly all glycolytic genes. The pentose phosphate pathway (PPP) contributes to the production of nicotinamide adenine dinucleotide phosphate (NADPH). Although the expression of PPP genes and intracellular NADPH were decreased by Ad4BP/SF-1 knockdown, these genes were not the direct targets of Ad4BP/SF-1. This study therefore investigates whether Ad4BP/SF-1 directly regulates genes implicated in NADPH production. Examination of previously published data sets of mRNA sequence (mRNA-seq) and ChIP-seq strongly suggested a possibility that other NADPH-producing genes, such as malic enzyme 1 (Me1) and methylenetetrahydrofolate dehydrogenase 2 (Mthfd2), are the direct targets of Ad4BP/SF-1. Reporter gene assays and determination of intracellular NADPH concentration supported the notion that Ad4BP/SF-1 regulates NADPH production by regulating these genes. NADPH is required for macromolecule synthesis of compounds such as steroids, and for detoxification of reactive oxygen species. When synthesizing steroid hormones, steroidogenic cells consume NADPH through enzymatic reactions mediated by steroidogenic P450s. NADPH is also consumed through elimination of reactive oxygen species produced as the byproducts of the P450 reactions. Overall, Ad4BP/SF-1 potentially maintains the intracellular NADPH level through cooperative regulation of genes involved in the biological processes for consumption and supply.
authors.affiliation: Division of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyabayashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shima
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ichinose
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miura
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohkawa
authors.forename: Mikita
authors.initials: M
authors.lastname: Suyama
authors.forename: Ken-Ichirou
authors.initials: KI
authors.lastname: Morohashi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000302:Adrenal Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D000619:Aminohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009249:NADP / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011993:Recombinant Fusion Proteins; D054339:Steroidogenic Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D054339:Steroidogenic Factor 1; C055342:methylene tetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase; C515058:steroidogenic factor 1, mouse; D009249:NADP; D008291:Malate Dehydrogenase; C030574:malate dehydrogenase (decarboxylating); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases