Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage.

Carla Iacobini,Giuseppe Pugliese,Martina Vitale,Stefano Menini

doi:10.3390/biomedicines9091139

Carla Iacobini, Giuseppe Pugliese + Show 2 more

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https://doi.org/10.3390/biomedicines9091139

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Journal: Biomedicines	Publication Date: Sep 2, 2021
Citations: 13	License type: CC BY 4.0

Affiliation: Sapienza University of Rome

Abstract

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

Highlights

This study aimed at investigating whether high glucose (HG) conditions induce HIF1α activity and related cellular energetic changes (i.e., Warburg effect), which may serve as initial mediators of glucose toxicity by activating the alternative pathways of glucose metabolism involved in hyperglycemia-induced vascular damage
A weak and late effect on hypoxia inducible factor (HIF)-1α mRNA levels was observed in LPS-stimulated U937 cells (Figure 1G), confirming that glucoseinduced Hypoxia-inducible factor-1α (HIF-1α) nuclear translocation can be accounted for by protein changes, not by transcriptional regulation
HIF-1α-dependent metabolic reprogramming induced by HG resembled the Warburg effect, as glucose flux was shifted from mitochondrial oxidation to glycolysis and lactate production

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The injurious effect of hyperglycemia was attributed to biochemical consequences of intracellular metabolism of excess glucose. According to Brownlee’s unifying hypothesis, biochemical abnormalities are triggered by mitochondrial superoxide overproduction resulting from hyperglycemiainduced increase in electron donors from the tricarboxylic acid cycle. At variance with previous reports showing increased superoxide levels [4], recent evidence suggests that superoxide production and mitochondrial function are decreased in the diabetic kidney [5,6]. The role of mitochondrial superoxide as the initial trigger of these ominous changes has been put into question [7,8]. The unifying hypothesis of diabetic complications may need an alternative mechanism for instigating two main metabolic changes, Biomedicines 2021, 9, 1139.

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