Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes

Abstract

Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain–containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes1. Although Hif regulates many metabolic pathways2, it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3, also known as Egln3, improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.

HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

“…Increased expression of the Hif-2a target Irs2 in the liver of mice with acute hepatic Hif-p4h-3 deletion was accompanied by a decreased Srebp1c expression (26). The present results indicating weak stabilization of Hif2a, increased expression of Irs2, and decreased expression of Srebp1c and its targets Acca and Fas in the Hif-p4h-2 gt/gt liver agree with those data.…”

“…Extensive liver-specific stabilization of Hif-2a leads to hepatic steatosis (26,28). However, the Hif-p4h-2 gt/gt mice in the present study showed no steatosis but were instead protected against it.…”

“…However, the Hif-p4h-2 gt/gt mice in the present study showed no steatosis but were instead protected against it. Liver-specific stabilization of Hif-2a by acute Hif-p4h-3 deletion likewise did not lead to hepatic steatosis, suggesting that low-level hepatic Hif-2a stabilization, as found in the present Hif-p4h-2 gt/gt mice, has beneficial effects, whereas extensive hepatic Hif-2a stabilization leads to steatosis (26,28).…”

“…Acute hepatic Hif-p4h-3 deletion has also been reported to improve glucose tolerance and insulin sensitivity, but no data were available on its effects on weight gain or serum cholesterol levels (26).…”

“…5B). The mRNA level of the HIF-2a target Irs2 (26), which regulates Srepb1c and hepatic lipid accumulation (27), was increased in the Hif-p4h-2 gt/gt liver, whereas the mRNA level of Irs1 was not altered (Fig. 5B).…”