Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma

Abstract Excessive fructose intake causes a variety of adverse conditions (e.g., obesity, hepatic steatosis, insulin resistance and uric acid overproduction). Particularly, high fructose-induced hypertension is the most common and significant pathological setting, however, its underlying mechanisms are not established. We investigated these mechanisms in 7-week-old male SD rats fed a diet containing 60% glucose (GLU) or 60% fructose (FRU) for 3, 6, or 12 weeks. Daily food consumption was measured to avoid between-group discrepancies in caloric/salt intake, adjusting for feeding amounts. The FRU rats' mean blood pressure was significantly higher and fractional sodium excretion (FENa) was significantly lower, indicating that the high-fructose diet caused salt retention. The FRU rats' kidney weight and glomerular surface area were greater, suggesting that the high-fructose diet induced an increase in extracellular fluid volume. The GLUT5 and ketohexokinase expressions, an enzyme required for fructose metabolism, were up-regulated in FRU. Cortical ATP levels were significantly lower in FRU, which might indicate ATP consumption due to fructose metabolism. Unlike previous reports, the high-fructose diet did not affect NHE3 expression. A gene chip analysis conducted to identify susceptible molecules revealed that only Slc5a10 (corresponding to SGLT5) in FRU showed >2-fold up-regulation versus GLU. RT-PCR and in situ hybridization confirmed the SGLT5 up-regulation. Our findings may indicate that the high-fructose diet increased sodium reabsorption principally through up-regulated SGLT5, finally causing salt-sensitive hypertension.

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Non-dietary Fructose Metabolism Contributes to the Warburg effect in Cancers

10.1101/2020.06.04.132902 ◽

2020 ◽

Author(s):

Bing Han ◽

Lu Wang ◽

Meilin Wei ◽

Cynthia Rajani ◽

Runming Wei ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Glucose Transporter ◽

Self Control ◽

Metabolic Reprogramming ◽

Atp Production ◽

Fructose Metabolism ◽

Energy Needs ◽

Dietary Fructose ◽

The Warburg Effect

AbstractFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream. Therefore, it remains unclear how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the cancer cells can convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and causes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancers. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study identified overlooked fructose resources for cancer cells as an essential part of their metabolic reprogramming and caused the Warburg effect.Statement of SignificanceOur findings in this study suggest that the Warburg effect is actually achieved by means of fructose metabolism, instead of glucose metabolism alone. Fructose metabolism results in accelerated glycolysis and an increased amount of ATP and key intermediates for anabolic metabolism.

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Acute interactions between intestinal sugar and calcium transport in vitro

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00263.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. G1-G12 ◽

Cited By ~ 10

Author(s):

Phuntila Tharabenjasin ◽

Veronique Douard ◽

Chirag Patel ◽

Nateetip Krishnamra ◽

Richard J. Johnson ◽

...

Keyword(s):

Transient Receptor Potential ◽

Glucose Transporter ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Wild Type ◽

Fructose Metabolism ◽

Voltage Dependent ◽

Selective Channel ◽

Transient Receptor

Fructose consumption by Americans has increased markedly, whereas Ca2+ intake has decreased below recommended levels. Because fructose metabolism decreases enterocyte ATP concentrations, we tested the hypothesis that luminal fructose acutely reduces active, diet-inducible Ca2+ transport in the small intestine. We confirmed that the decrease in ATP concentrations was indeed greater in fructose- compared with glucose-incubated mucosal homogenates from wild-type and was prevented in fructose-incubated homogenates from ketohexokinase (KHK)−/− mice. We then induced active Ca2+ transport by chronically feeding wild-type, fructose transporter glucose transporter 5 (GLUT5)−/−, as well as KHK−/− mice a low Ca2+ diet and measured transepithelial Ca2+ transport in everted duodenal sacs incubated in solutions containing glucose, fructose, or their nonmetabolizable analogs. The diet-induced increase in active Ca2+ transport was proportional to dramatic increases in expression of the Ca2+-selective channel transient receptor potential vanilloid family calcium channel 6 as well as of the Ca2+-binding protein 9k (CaBP9k) but not that of the voltage-dependent L-type channel Ca(v)1.3. Crypt-villus distribution of CaBP9k seems heterogeneous, but low Ca2+ diets induce expression in more cells. In contrast, KHK distribution is homogeneous, suggesting that fructose metabolism can occur in all enterocytes. Diet-induced Ca2+ transport was not enhanced by addition of the enterocyte fuel glutamine and was always greater in sacs of wild-type, GLUT5−/−, and KHK−/− mice incubated with fructose or nonmetabolizable sugars than those incubated with glucose. Thus duodenal Ca2+ transport is not affected by fructose and enterocyte ATP concentrations but instead may decrease with glucose metabolism, as Ca2+ transport remains high with 3- O-methylglucose that is also transported by sodium-glucose cotransporter 1 but cannot be metabolized.

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HIF1-α-Mediated Gene Expression Induced by Vitamin B1 Deficiency

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000159 ◽

2013 ◽

Vol 83 (3) ◽

pp. 188-197 ◽

Cited By ~ 21

Author(s):

Rebecca L. Sweet ◽

Jason A. Zastre

Keyword(s):

Gene Expression ◽

Thiamine Deficiency ◽

Glucose Transporter ◽

Neuroblastoma Cell ◽

Hypoxia Inducible Factor ◽

Clinical Manifestations ◽

Vitamin B1 ◽

Low Oxygen ◽

Glucose Transporter 1 ◽

Metabolic Intermediates

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

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Early-Onset Absence Epilepsy Caused by Mutations in the Glucose Transporter GLUT1

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(09)79174-4 ◽

2010 ◽

Vol 2010 ◽

pp. 42-43

Author(s):

M.J. Brodie

Keyword(s):

Early Onset ◽

Glucose Transporter ◽

Absence Epilepsy ◽

Glucose Transporter Glut1 ◽

Transporter Glut1

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Glucose transporter isoform 1 (GLUT1) expression enhances formation and growth of hepatic metastases

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1332075 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

A Koch ◽

P Wild ◽

M Kreutz ◽

A Bosserhoff ◽

C Hellerbrand

Keyword(s):

Glucose Transporter ◽

Hepatic Metastases ◽

Glut1 Expression

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A Case of Congenital Glucose Galactose Malabsorption with a New Mutation in the SLC5A1 Gene

Journal of Pediatric Genetics ◽

10.1055/s-0040-1719161 ◽

2020 ◽

Author(s):

Hasan Akduman ◽

Dilek Dilli ◽

Serdar Ceylaner

Keyword(s):

Mutation Analysis ◽

Autosomal Recessive ◽

Glucose Transporter ◽

Neonatal Period ◽

Autosomal Recessive Disorder ◽

Homozygous Mutation ◽

New Mutation ◽

Early Neonatal Period ◽

Sodium Dependent ◽

Hypernatremic Dehydration

AbstractCongenital glucose-galactose malabsorption (CGGM) is an autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. It was sourced from a mutation in the SLC5A1 gene, which encodes a sodium-dependent glucose transporter. Here we report a 2-day-old girl with CGGM who presented with severe hypernatremic dehydration due to diarrhea beginning in the first hours of life. Mutation analysis revealed a novel homozygous mutation NM_000343.3 c.127G > A (p.Gly43Arg) in the SLC5A1 gene. Since CGGM can cause fatal diarrhea in the early neonatal period, timely diagnosis of the disease seems to be essential.

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