HIF regulates Kidney Glycogen Synthesis | PHD Biology

Kidney Int. 2020 Apr;97(4):645-647. doi:10.1016/j.kint.2019.11.036.

Got Glycogen? An Energy Resource in HIF-mediated Prevention of Ischemic Kidney Injury.

Commentary: Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage

Haase VH

Hypoxia-inducible factor activation reprograms glucose metabolism and leads to glycogen accumulation in multiple cell types. In the April of 2020 issue of Kidney International, Ito and colleagues demonstrate that pharmacologic inhibition of hypoxia-inducible factor–prolyl hydroxylase domain oxygen sensors in renal epithelial cells enhances glycogen synthesis and protects from subsequent hypoxia and glucose deprivation. In vivo studies advance the concept that renal glycogen metabolism contributes to cytoprotection afforded by pre-ischemic hypoxia-inducible factor–prolyl hydroxylase domain inhibition.

The inducing role of hypoxia and HIF-1 in the regulation of glycogen storage has been previously established in neoplastic and non-neoplastic cells and occurs at multiple levels of glycogen metabolism.5 When glucose is taken up by cells, it is phosphorylated and con- verted from glucose-6-phosphate to glucose-1-phosphate (PGM1), and then via the action of UTP:glucose-1- phosphate uridylyltransferase (UGP) is conjugated to UDP at carbon position 1 (UDP-glucose). Activated UDP- glucose is then incorporated into glycogen particles through a1-4 linkage (GYS1). Once a certain chain length has been reached, the outer a1,4-linked glucosyl unit is transferred to form an a1-6 glycosidic bond on the same or an adjacent chain (GBE1), thereby enhancing glycogen solubility. Whereas hypoxia and/or HIF stimulate the expression of genes encoding enzymes directly involved in glycogen synthesis (PGM1, UGP2, GYS1, and GBE1), HIF- regulated protein phosphatase 1 regulatory subunit 3C (PPP1RC3) increases glycogen accumulation, presumably by inhibiting the catalytic activity of glycogen phosphorylase, which is the rate-limiting step in glycogenolysis. Taken together, these findings provide support for the concept that hypoxia via HIF-1, in addition to promoting glucose uptake and shifting metabolism toward increased glucose consumption and glycolysis, promotes glucose and energy storage in the form of glycogen. This response may appear paradoxical at first, as cells are less likely to divert energy resources to biochemical storage reactions when challenged energetically under acute hypoxic conditions. However, once adaptation to prolonged hypoxia and metabolic reprogramming has occurred, cells will need to rebuild glycogen stores. Increased glycogen reserves would allow cells to better cope with subsequent hypoxic and/or glucose-depleted conditions by increasing adenosine triphosphate availability. In the setting of cancer, this has been proposed to help neoplastic cells survive and metastasize in harsh microenvironments.

(click on image to view commentary)

link to paper by Ito and colleagues in Kidney International, April 2020