title: Low oxygen level increases proliferation and metabolic changes in bovine granulosa cells.
abstract: The present study addresses molecular backgrounds underlying low oxygen induced metabolic changes and 1.2-fold change in bovine granulosa cell (GCs) proliferation. RNA-seq revealed that low oxygen (5%) upregulated genes associated with HIF-1 and glycolysis and downregulated genes associated with mitochondrial respiration than that in high oxygen level (21%). Low oxygen level induced high glycolytic activity and low mitochondrial function and biogenesis. Low oxygen level enhanced GC proliferation with high expression levels of HIF-1, VEGF, AKT, mTOR, and S6RP, whereas addition of anti-VEGF antibody decreased cellular proliferation with low phosphorylated AKT and mTOR expression levels. Low oxygen level reduced SIRT1, whereas activation of SIRT1 by resveratrol increased mitochondrial replication and decreased cellular proliferation with reduction of phosphorylated mTOR. These results suggest that low oxygen level stimulates the HIF1-VEGF-AKT-mTOR pathway and up-regulates glycolysis, which contributes to GC proliferation, and downregulation of SIRT1 contributes to hypoxia-associated reduction of mitochondria and cellular proliferation.
authors: Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan.
authors: Shogo
authors: S
authors: Shiratsuki
authors: Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan.
authors: Tomotaka
authors: T
authors: Hara
authors: Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan.
authors: Yasuhisa
authors: Y
authors: Munakata
authors: Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan.
authors: Koumei
authors: K
authors: Shirasuna
authors: Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan.
authors: Takehito
authors: T
authors: Kuwayama
authors: Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan. Electronic address: h1iwata@nodai.ac.jp.
authors: Hisataka
authors: H
authors: Iwata
mesh_terms: D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006107:Granulosa Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D001678:Organelle Biogenesis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D056564:Sirtuin 1; D010100:Oxygen
keywords: Cellular proliferation; Granulosa cell; Low oxygen; Metabolism