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Sci Rep. 2018 Sep 24;8(1):14290. doi: 10.1038/s41598-018-32575-z.

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

Author information

1
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
2
Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, 211-8533, Japan.
3
Metabolism and Nutrition Research Unit, Innovative Integrated Bio-research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-8641, Japan.
4
Department of Diabetic Complications, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
5
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
6
Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, 654-0142, Japan.
7
National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
8
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan. mmatsumoto@ri.ncgm.go.jp.

Abstract

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.

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