PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes

• Published in: Scientific reports 2018-09, Vol.8 (1), p.14290-16, Article 14290
• Main Authors: Yano, Hiroyuki, Sakai, Mashito, Matsukawa, Toshiya, Yagi, Takashi, Naganuma, Takao, Mitsushima, Masaru, Iida, Satoshi, Inaba, Yuka, Inoue, Hiroshi, Unoki-Kubota, Hiroyuki, Kaburagi, Yasushi, Asahara, Shun-ichiro, Kido, Yoshiaki, Minami, Shiro, Kasuga, Masato, Matsumoto, Michihiro
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/89; 38; 38/70; 38/77; 631/337/572/2102; 64; 64/110; 64/60; 692/163/2743/137/773; 692/4017; 82; 82/29; 82/80; 96; 96/1; 96/106; 96/109; Cyclic AMP response element-binding protein; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Event-related potentials; Glucagon; Gluconeogenesis; Glucose; Glucose metabolism; Hepatocytes; Homeostasis; Humanities and Social Sciences; Insulin; Kinases; Liver; Metabolism; multidisciplinary; Procollagen-proline dioxygenase; Proline; Prolyl hydroxylase; Protein kinase A; Proteins; Science; Science (multidisciplinary); Signal transduction; Transcription
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-32575-z

Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate ( Irs )2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element-binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain ( PHD )3, which suppressed stress signalling through inhibition of the IκB kinase–nuclear factor-κB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator–activated receptor γ coactivator 1α-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.