Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells

Sakagami, Hidemitsu; Makino, Yuichi; Mizumoto, Katsutoshi; Isoe, Tsubasa; Takeda, Yasutaka; Watanabe, Jun; Fujita, Yukihiro; Takiyama, Yumi; Abiko, Atsuko; Haneda, Masakazu

doi:10.1152/ajpendo.00597.2012

Cited by 63 publications

(53 citation statements)

References 29 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It should be noted that addition of the vehicle control (DMSO) in the inhibitor studies yielded alterations in the relative amounts of glucose uptake when compared to non-DMSO treated cells (Figure 1A). STAT3 has previously been shown to mediate glucose up through HIF1α induced translocation of GLUT4 (Demaria et al, 2010; Sakagami et al, 2014). Indeed IL-15 induced an increase in mRNA expression levels of HIF1α and these effects were prevented with STAT3 inhibition in the presence of IL-15 ( P < 0.05; Figure 5C).…”

Section: Resultsmentioning

confidence: 99%

IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

2016

View full text Add to dashboard Cite

Myokines are specialized cytokines that are secreted from skeletal muscle (SKM) in response to metabolic stimuli, such as exercise. Interleukin-15 (IL-15) is a myokine with potential to reduce obesity and increase lean mass through induction of metabolic processes. It has been previously shown that IL-15 acts to increase glucose uptake in SKM cells. However, the downstream signals orchestrating the link between IL-15 signaling and glucose uptake have not been fully explored. Here we employed the mouse SKM C2C12 cell line to examine potential downstream targets of IL-15-induced alterations in glucose uptake. Following differentiation, C2C12 cells were treated overnight with 100 ng/ml of IL-15. Activation of factors associated with glucose metabolism (Akt and AMPK) and known downstream targets of IL-15 (Jak1, Jak3, STAT3, and STAT5) were assessed with IL-15 stimulation. IL-15 stimulated glucose uptake and GLUT4 translocation to the plasma membrane. IL-15 treatment had no effect on phospho-Akt, phospho-Akt substrates, phospho-AMPK, phospho-Jak1, or phospho-STAT5. However, with IL-15, phospho-Jak3 and phospho-STAT3 levels were increased along with increased interaction of Jak3 and STAT3. Additionally, IL-15 induced a translocation of phospho-STAT3 from the cytoplasm to the nucleus. We have evidence that a mediator of glucose uptake, HIF1α, expression was dependent on IL-15 induced STAT3 activation. Finally, upon inhibition of STAT3 the positive effects of IL-15 on glucose uptake and GLUT4 translocation were abolished. Taken together, we provide evidence for a novel signaling pathway for IL-15 acting through Jak3/STAT3 to regulate glucose metabolism.

show abstract

Section: Resultsmentioning

confidence: 99%

IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

2016

View full text Add to dashboard Cite

show abstract

“…We explored a potential role for these transcription factors in arsenite-induced glycolysis and found that only HIF-1α was required for arsenite-induced glycolysis. In skeletal muscle cells, translocation of Glut-4 from intracellular vesicles to the plasma membrane is a necessary step for glycolysis [12]. Indeed, accumulation of Glut-4 in the plasma membrane fraction of the L-02 cells was increased by their exposure to arsenite; this effect was blocked by HIF-1α knockdown.…”

Section: Discussionmentioning

confidence: 99%

“…HIFs are sensitive to environmental factors, especially arsenite, and, under normoxic conditions, they are involved in the regulation of a variety of cellular functions and thereby contribute to various malignancies [8,9]. HIF-α binds to hypoxia response elements (HREs) of target genes for vascular endothelial growth factor [10], glycolytic enzymes [11], and glucose transporters [12,13], which are related to aspects of cancer growth, including proliferation, angiogenesis, and glycolysis. HIF-α expression is also increased, however, under certain normoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Luo

Liu

Ling

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

show abstract

“…Therefore, we speculated that intrinsic ACh synthesized by ChAT-expressing cells also may have a role similar to that of extrinsic ACh. HIF-1α is a master transcription factor responsible for glucose metabolism, including glycolysis and glucose uptake and utilization [9,10,11]. Thus, increased ACh levels in ChAT-expressing cells may have a crucial role in upregulating the HIF-1α protein level and promote cells to use glucose more efficiently.…”

Section: Discussionmentioning

confidence: 99%

A Non-Neuronal Cholinergic System Regulates Cellular ATP Levels to Maintain Cell Viability

Oikawa

Iketani

Kakinuma

2014

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: We previously suggested that a non-neuronal cholinergic system modulates energy metabolism through the mitochondria. However, the mechanisms responsible for making this system crucial remained undetermined. Methods: In this study, we developed a fusion protein expression vector containing a luciferase gene fused to the folic acid receptor-α gene. Results: This protein of the vector was confirmed to target the plasma membrane of transfected HEK293 cells, and vector-derived luciferase activities and ATP levels in viable cells were positively correlated (r = 0.599). Using this luciferase vector, choline acetyltransferase (ChAT)-expressing cells (i.e., cells with an activated non-neuronal cholinergic system) had increased cellular ATP levels. ChAT-expressing cells also had upregulated IGF-1R and Glut-1 protein expressions as well as increased glucose uptake. This activated non-neuronal cholinergic system with efficient glucose metabolism rendered cells resistant to serum depletion-induced cell death. Conclusion: Our results indicate that a non-neuronal cholinergic system is involved in sustaining ATP levels to render cells resistant to a nutrient-deficient environment.

show abstract

Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells

Abstract: Abiko A, Haneda M. Loss of HIF-1␣ impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells.

Cited by 63 publications

References 29 publications

IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

A Non-Neuronal Cholinergic System Regulates Cellular ATP Levels to Maintain Cell Viability

Contact Info

Product

Resources

About