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Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension.

ABSTRACT: The identity of the transporter responsible for fructose absorption in the intestine in vivo and its potential role in fructose-induced hypertension remain speculative. Here we demonstrate that Glut5 (Slc2a5) deletion reduced fructose absorption by approximately 75% in the jejunum and decreased the concentration of serum fructose by approximately 90% relative to wild-type mice on increased dietary fructose. When fed a control (60% starch) diet, Glut5(-/-) mice had normal blood pressure and displayed normal weight gain. However, whereas Glut5(+/+) mice showed enhanced salt absorption in their jejuna in response to luminal fructose and developed systemic hypertension when fed a high fructose (60% fructose) diet for 14 weeks, Glut5(-/-) mice did not display fructose-stimulated salt absorption in their jejuna, and they experienced a significant impairment of nutrient absorption in their intestine with accompanying hypotension as early as 3-5 days after the start of a high fructose diet. Examination of the intestinal tract of Glut5(-/-) mice fed a high fructose diet revealed massive dilatation of the caecum and colon, consistent with severe malabsorption, along with a unique adaptive up-regulation of ion transporters. In contrast to the malabsorption of fructose, Glut5(-/-) mice did not exhibit an absorption defect when fed a high glucose (60% glucose) diet. We conclude that Glut5 is essential for the absorption of fructose in the intestine and plays a fundamental role in the generation of fructose-induced hypertension. Deletion of Glut5 results in a serious nutrient-absorptive defect and volume depletion only when the animals are fed a high fructose diet and is associated with compensatory adaptive up-regulation of ion-absorbing transporters in the colon.

SUBMITTER: Barone S

PROVIDER: S-EPMC2643499 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension.

Barone Sharon S Fussell Stacey L SL Singh Anurag Kumar AK Lucas Fred F Xu Jie J Kim Charles C Wu Xudong X Yu Yiling Y Amlal Hassane H Seidler Ursula U Zuo Jian J Soleimani Manoocher M

The Journal of biological chemistry 20081217 8

The identity of the transporter responsible for fructose absorption in the intestine in vivo and its potential role in fructose-induced hypertension remain speculative. Here we demonstrate that Glut5 (Slc2a5) deletion reduced fructose absorption by approximately 75% in the jejunum and decreased the concentration of serum fructose by approximately 90% relative to wild-type mice on increased dietary fructose. When fed a control (60% starch) diet, Glut5(-/-) mice had normal blood pressure and displ ...[more]

PMID: 19091748

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Project description:BackgroundFructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that acquire the ability to metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation.MethodsLive cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to "train" non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containing KHK-specific sgRNA was transfected in 293T cells to generate KHK-/- cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose.ResultsWe found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability. SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK).ConclusionsWe show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

Dataset Information

Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension.

Publications

Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension.

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