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Pterosin B Has Multiple Targets in Gluconeogenic Programs, Including Coenzyme Q in RORα-SRC2 Signaling

Pterosin B Has Multiple Targets in Gluconeogenic Programs, Including Coenzyme Q in RORα-SRC2 Signaling

Yumi Itoh, Hiroyuki Fuchino, Masato Sanosaka, Koichiro Kako, Kazumasa Hada, Akiyoshi Fukamizu, Hiroshi Takemori, Nobuo Kawahara

Biochem Biophys Res Commun. 2016 Apr 29;473(2):415-20.

PMID: 26970301

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP34175967	Pterosin B		34175-96-7	Price

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