The Fast Lane of Hypoxic Adaptation: Glucose Transport Is Modulated via A HIF-Hydroxylase-AMPK-Axis in Jejunum Epithelium

Abstract

The intestinal epithelium is able to adapt to varying blood flow and, thus, oxygen availability. Still, the adaptation fails under pathologic situations. A better understanding of the mechanisms underlying the epithelial adaptation to hypoxia could help to improve the therapeutic approach. We hypothesized that the short-term adaptation to hypoxia is mediated via AMP-activated protein kinase (AMPK) and that it is coupled to the long-term adaptation by a common regulation mechanism, the HIF-hydroxylase enzymes. Further, we hypothesized the transepithelial transport of glucose to be part of this short-term adaptation. We conducted Ussing chamber studies using isolated lagomorph jejunum epithelium and cell culture experiments with CaCo-2 cells. The epithelia and cells were incubated under 100% and 21% O2, respectively, with the panhydroxylase inhibitor dimethyloxalylglycine (DMOG) or under 1% O2. We showed an activation of AMPK under hypoxia and after incubation with DMOG by Western blot. This could be related to functional effects like an impairment of Na+-coupled glucose transport. Inhibitor studies revealed a recruitment of glucose transporter 1 under hypoxia, but not after incubation with DMOG. Summing up, we showed an influence of hydroxylase enzymes on AMPK activity and similarities between hypoxia and the effects of hydroxylase inhibition on functional changes.

Activation of AMPK under Hypoxia: Many Roads Leading to Rome

“…Therefore, it would be convenient if AMPK was regulated by the same hydroxylation mechanisms under hypoxia, orchestrating a common adaptation reaction. Indeed, we could previously show an activation of AMPK in CaCo-2 cells both under hypoxia and upon treatment with the pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) [44]. In line, Yan et al [84] were able to induce an activation of AMPK in cardiomyocytes by application of DMOG or siRNA for HIF-P4H 2.…”

“…An activation of AMPK under hypoxia has been demonstrated in various tissues and cell types, ranging from brain [32][33][34], liver [35] and skeletal muscle [36][37][38] to cardiomyocytes [39,40], alveolar epithelial cells [41,42], intestinal epithelial cells [43,44] and fibroblasts [45]. Interestingly, an inhibition of AMPK activation under hypoxia was reported after long-term hypoxia (in this case 8% oxygen for 12 d) [46].…”

“…An interrelated regulation of both mediators could help to orchestrate their concerted adaptation reaction. It has been reported that AMPK regulates transport mechanisms on the protein level, which are also targets for HIF1 on the transcriptional level, e.g., Na + /K + -ATPase, facilitated glucose transporters (GLUT) or Na + -coupled glucose transporter (SGLT1) and thus protects the cells from hypoxic damage [38,42,44,99].…”

Adaptation to Hypoxia: A Chimera?

“…Still, adaptation may fail under pathologic situations that include hypoperfusion and inflammatory disease. The jejunum epithelium model was used by Dengler and Gable [4] to verify that the short-term adaptation to hypoxia is mediated by upregulation of the AMP-activated protein kinase (AMPK), which precedes the classical HIF-mediated adaptation, and acts primarily by modulating the transepithelial Na + -glucose cotransport via SGLT1. This observation adds to the complex interplay between hypoxia signaling and the various outcomes.…”

Electric field down-regulates CD9 to promote keratinocytes migration through AMPK pathway

“…Recently, an AMPK activator met has been shown to reduce cell proliferation and delay wound healing [20], suggesting that AMPK may be involved in the cytobiology of keratinocytes during wound repair. Coincidentally, AMPK participates in epidermal migration in the early stage of wound under hypoxic environment, and AMPK inhibition significantly enhances the motor ability of keratinocytes [21]. Additionally, AMPK activity in tibialis anterior (TA) muscle was attenuated under high-frequency electric stimulation [22].…”