The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

Abstract

Recent reports indicate that the hypoxia-induced factor (HIF1α) and the Warburg effect play an initiating role in glucotoxicity, which underlies disorders in metabolic diseases. WWOX has been identified as a HIF1α regulator. WWOX downregulation leads to an increased expression of HIF1α target genes encoding glucose transporters and glycolysis’ enzymes. It has been proven in the normoglycemic mice cells and in gestational diabetes patients. The aim of the study was to determine WWOX’s role in glucose metabolism regulation in hyperglycemia and hypoxia to confirm its importance in the development of metabolic disorders. For this purpose, the WWOX gene was silenced in human normal fibroblasts, and then cells were cultured under different sugar and oxygen levels. Thereafter, it was investigated how WWOX silencing alters the genes and proteins expression profile of glucose transporters and glycolysis pathway enzymes, and their activity. In normoxia normoglycemia, higher glycolysis genes expression, their activity, and the lactate concentration were observed in WWOX KO fibroblasts in comparison to control cells. In normoxia hyperglycemia, it was observed a decrease of insulin-dependent glucose uptake and a further increase of lactate. It likely intensifies hyperglycemia condition, which deepen the glucose toxic effect. Then, in hypoxia hyperglycemia, WWOX KO caused weaker glucose uptake and elevated lactate production. In conclusion, the WWOX/HIF1A axis downregulation alters glucose metabolism and probably predispose to metabolic disorders.

WWOX and metabolic regulation in normal and pathological conditions

“…In addition, under hypoxic hyperglycemic conditions, HIF1α transactivation function was increased in WWOX KO cells, and increases in the expression of its target genes PFK, PKM2, and PDK were observed. Simultaneously, an increase in lactate concentration has been noted [74].…”

“…Over the past decade, an increasing number of reports indicating the role of WWOX in the regulation of glucose metabolism have emerged [14,15,26,74]. In light of the increasing incidence of sugar metabolism disorders among different human populations, gaining more knowledge about the genes and mechanisms contributing to its pathophysiology is necessary.…”

“…Our further analysis of the importance of WWOX in glucose metabolism in a human fibroblast cell line revealed that in normoxic and normoglycemic conditions, WWOX deficiency leads to increased HIF1A mRNA and protein expression. Additionally, it increases the translocation of HIF1A to the nucleus and amplifies its transactivation function [74]. The expression levels of SLC2A1, ENO1, PKM2, PDK, and SLC2A4 were increased in WWOX KO cells, and insulindependent and insulin-independent glucose uptake, hexokinase, and lactate dehydrogenase enzymatic activities were upregulated.…”

“…This clearly indicates that WWOX silencing leads to a shift toward anaerobic glycolysis under normoxic conditions. In terms of its importance in diabetes, studies in hyperglycemic conditions also found that, although fibroblasts are not typical insulin target cells and show little metabolic response to insulin, the level of insulin-dependent glucose uptake under hyperglycemic culture conditions was several times lower in WWOX KO cells than in control cells [74]. In addition, under hypoxic hyperglycemic conditions, HIF1α transactivation function was increased in WWOX KO cells, and increases in the expression of its target genes PFK, PKM2, and PDK were observed.…”

Comparative transcriptomics of high-altitude Vulpes and their low-altitude relatives

“…Furthermore, V. ferrilata have more PSGs that may be related to coping with the selection pressure of plateau environment compared with V. v. montana (Table 3). Among these 111 PSGs in V. ferrilata, 20 PSGs related to high-altitude environmental selection stress mainly include the following five aspects: DNA damage repair (LIG4, ZNF830, CRTAC1, and GRB2) (Jun et al, 2016;Chen G. et al, 2018;Hou et al, 2019;Félix et al, 2021), energy metabolism (ARF6 and IRS1) (Dong et al, 2006;Gamara et al, 2021), myocardial growth (EIF3A, IL6ST, SIRT4, and MZB1) (Luo et al, 2016;Klimushina et al, 2019;Miao et al, 2019;Zhang et al, 2021), angiogenesis (IGFBP3, RND3, APLNR, RBPJ, and ARHGEF15) (Lofqvist et al, 2007;Kusuhara et al, 2012;Díaz-Trelles et al, 2016;Mastrella et al, 2019;Wu et al, 2021), and hypoxia stress response (RHEB, WWOX, COMMD1, LAMA4, and PNN) (He et al, 2017;Murata et al, 2017;Hsu et al, 2020;Baryla et al, 2022;Cai et al, 2022). In contrast, PSGs related to altitude adaptation in V. v. montana only has DNA damage repair (C19ORF57) (Takemoto et al, 2020) and hypoxia response related to HIF1-α regulation (FUT11, USP8, CASP14, VGLL4, and ALS2) (Troilo et al, 2014;Ye et al, 2018;Rivas et al, 2020;Wang et al, 2020;Ruan et al, 2021).…”