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.
Highlights
Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis
PHD3 expression is regulated by glucagon–cAMP–PKA signalling in hepatocytes
We show that PHD3—whose expression is upregulated by glucagon–cAMP signalling through the GCN5–CITED2–PKA signalling module—is a critical component of cAMP-induced gluconeogenesis and insulin signal transduction, two key processes for maintaining glucose homeostasis in both fasting and postprandial states
Summary
Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. In obese and diabetic individuals, chronic nutrient excess alters the production of pro- and anti-inflammatory adipokines, cytokines, and lipid mediators that activate a vast array of stress signalling pathways through c-Jun N-terminal kinase (JNK)[19], inhibitor of nuclear factor (NF)-κB (IκB) kinase (IKK)[20], and mechanistic target of rapamycin (mTOR) These pathways cooperatively induce chronic low-grade tissue inflammation and impair insulin action via kinase-dependent serine/threonine phosphorylation of IRS21. In the liver, enhanced glucagon and impaired insulin signalling promote hepatic gluconeogenesis through induction of gluconeogenic genes Both glucagon and stress signalling pathways are simultaneously activated under these pathological conditions, it is unclear how they crosstalk to regulate hepatocyte metabolism
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