title: Nuclear receptor 5A (NR5A) family regulates 5-aminolevulinic acid synthase 1 (ALAS1) gene expression in steroidogenic cells.
abstract: 5-Aminolevulinic acid synthase 1 (ALAS1) is a rate-limiting enzyme for heme biosynthesis in mammals. Heme is essential for the catalytic activities of P450 enzymes including steroid metabolic enzymes. Nuclear receptor 5A (NR5A) family proteins, steroidogenic factor-1 (SF-1), and liver receptor homolog-1 (LRH-1) play pivotal roles in regulation of steroidogenic enzymes. Recently, we showed that expression of SF-1/LRH-1 induces differentiation of mesenchymal stem cells into steroidogenic cells. In this study, genome-wide analysis revealed that ALAS1 was a novel SF-1-target gene in differentiated mesenchymal stem cells. Chromatin immunoprecipitation and reporter assays revealed that SF-1/LRH-1 up-regulated ALAS1 gene transcription in steroidogenic cells via binding to a 3.5-kb upstream region of ALAS1. The ALAS1 gene was up-regulated by overexpression of SF-1/LRH-1 in steroidogenic cells and down-regulated by knockdown of SF-1 in these cells. Peroxisome proliferator-activated receptor-γ coactivator-1α, a coactivator of nuclear receptors, also strongly coactivated expression of NR5A-target genes. Reporter analysis revealed that peroxisome proliferator-activated receptor-γ coactivator-1α strongly augmented ALAS1 gene transcription caused by SF-1 binding to the 3.5-kb upstream region. Finally knockdown of ALAS1 resulted in reduced progesterone production by steroidogenic cells. These results indicate that ALAS1 is a novel NR5A-target gene and participates in steroid hormone production.
authors.affiliation: Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Japan.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Ju
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizutani
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Imamichi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yazawa
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsumura
authors.forename: Shinya
authors.initials: S
authors.lastname: Kawabe
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kanno
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D000624:5-Aminolevulinate Synthetase