title: Pterosin B has multiple targets in gluconeogenic programs, including coenzyme Q in RORα-SRC2 signaling.
abstract: Hepatic gluconeogenic programs are regulated by a variety of signaling cascades. Glucagon-cAMP signaling is the main initiator of the gluconeogenic programs, including glucose-6-phosphatase catalytic subunit (G6pc) gene expression. Pterosin B, an ingredient in Pteridium aquilinum, inhibits salt-inducible kinase 3 signaling that represses cAMP-response element-binding protein regulated transcription coactivator 2, an inducer of gluconeogenic programs. As the results, pterosin B promotes G6pc expression even in the absence of cAMP. In this work, however, we noticed that once cAMP signaling was initiated, pterosin B became a strong repressor of G6pc expression. The search for associated transcription factors for pterosin B actions revealed that retinoic acid receptor-related orphan receptor alpha-steroid receptor coactivator 2 (RORα-SRC2) complex on the G6pc promoter was the target. Meanwhile, pterosin B impaired the oxidation-reduction cycle of coenzyme Q in mitochondrial oxidative phosphorylation (OXPHOS); and antimycin A, an inhibitor of coenzyme Q: cytochrome c-oxidoreductase (termed mitochondrial complex III), also mimicked pterosin B actions on RORα-SRC2 signaling. Although other respiratory toxins (rotenone and oligomycin) also suppressed G6pc expression accompanied by lowered ATP levels following the activation of AMP-activated kinase, minimal or no effect of these other toxins on RORα-SRC2 activity was observed. These results suggested that individual components in OXPHOS differentially linked to different transcriptional machineries for hepatic gluconeogenic programs, and the RORα-SRC2 complex acted as a sensor for oxidation-reduction cycle of coenzyme Q and regulated G6Pc expression. This was a site disrupted by pterosin B in gluconeogenic programs.
authors.affiliation: Cell Signaling and Metabolic Disease, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 305-0843, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fuchino
authors.affiliation: Cell Signaling and Metabolic Disease, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Sanosaka
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kako
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Hada
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.affiliation: Cell Signaling and Metabolic Disease, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan. Electronic address: mukuharu22@yahoo.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.affiliation: Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 305-0843, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kawahara
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D032498:Pteridium / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects*; D014451:Ubiquinone / Q000378:metabolism*
chemical_list: D007189:Indans; D051958:Nuclear Receptor Coactivator 2; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539739:Rora protein, mouse; C586064:pterosin B; D014451:Ubiquinone; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse; D005947:Glucose
keywords: Coenzyme Q; G6Pc; Gluconeogenesis; OXPHOS; RORα; SRC2