Abstract
The α-ketoglutarate–dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is an HIF target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. Although PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about the effects of this highly conserved enzyme in insulin-secreting β cells in vivo. Here, we show that the deletion of PHD3 specifically in β cells (βPHD3KO) was associated with impaired glucose homeostasis in mice fed a high-fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewired, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets was associated with impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes, and insulin secretion. Thus, PHD3 might be a pivotal component of the β cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.
Highlights
The prolyl-hydroxylase domain proteins (PHD1–3) encoded for by the Egl-9 homolog genes are α-ketoglutarate–dependent dioxygenases, which regulate cell function by catalyzing hydroxylation of peptidyl prolyl residues within various substrates using molecular oxygen [1,2,3,4]
We show that the α-ketoglutarate–dependent prolyl-4-hydroxylase 3 (PHD3) maintained β cell glucose sensing under states of metabolic stress associated with fatty acid abundance
Our data suggest that PHD3 is required for ensuring that acetyl-CoA derived from glycolysis preferentially feeds the TCA cycle, linking blood glucose levels with ATP/ADP generation, β cell electrical activity, and insulin secretion
Summary
The prolyl-hydroxylase domain proteins (PHD1–3) encoded for by the Egl-9 homolog genes are α-ketoglutarate–dependent dioxygenases, which regulate cell function by catalyzing hydroxylation of peptidyl prolyl residues within various substrates using molecular oxygen [1,2,3,4]. When oxygen concentration becomes limited, PHD activity decreases and HIF is stabilized, leading to dimerization with the β subunit and transcriptional regulation of target genes regulating the cellular response to hypoxia [5]. PHD3 has more recently been shown to hydroxylate and activate acetyl-CoA carboxylase 2 (ACC2), defined as the fatty acid oxidation gatekeeper, decreasing fatty acid breakdown and restraining myeloid cell proliferation during nutrient abundance [24]. Together, these studies place PHD3 as a central player in the regulation of glucose and fatty acid utilization with clear implications for metabolic disease risk
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