Intestinal Absorption of Fructose

Abstract

Increased understanding of fructose metabolism, which begins with uptake via the intestine, is important because fructose now constitutes a physiologically significant portion of human diets and is associated with increased incidence of certain cancers and metabolic diseases. New insights in our knowledge of intestinal fructose absorption mediated by the facilitative glucose transporter GLUT5 in the apical membrane and by GLUT2 in the basolateral membrane are reviewed. We begin with studies related to structure as well as ligand binding, then revisit the controversial proposition that apical GLUT2 is the main mediator of intestinal fructose absorption. The review then describes how dietary fructose may be sensed by intestinal cells to affect the expression and activity of transporters and fructolytic enzymes, to interact with the transport of certain minerals and electrolytes, and to regulate portal and peripheral fructosemia and glycemia. Finally, it discusses the potential contributions of dietary fructose to gastrointestinal diseases and to the gut microbiome.

Keywords: GLUT; carbohydrates; ligand recognition; metabolism; nutrition; sugars.

Figure 1

Intestinal fructose transport across the small intestinal epithelia. ❶ Dietary fructose (F) is transported across the apical membrane in monosaccharide form by a member of the facilitative GLUT family, GLUT5. Most fructose (solid arrow) exits the cytosol and enters the portal vein via basolateral GLUT2, which is also capable of transporting glucose and galactose (G) absorbed across the apical membrane by SGLT1 via Na⁺-coupled cotransport. Deletion of GLUT5 completely eliminates transepithelial fructose transport, while total or intestine-specific deletion of GLUT2 only modestly reduces glucose transport, for as yet unclear reasons. ❷ Some fructose is phosphorylated by KHK, thus keeping the lumen-to-cytosol gradient favorable for fructose uptake. Deletion of KHK reduces the transapical fructose transport rate. ❸ When luminal fructose concentrations are high, a product(s) of fructose metabolism (M) stimulate(s) transcription and translation of GLUT5 as well as fructolytic enzymes. Basolateral delivery of fructose via GLUT2 in GLUT5^−/− mice cannot induce increases in GLUT5 mRNA, suggesting that GLUT5 may also function as a transceptor. ❹ New GLUT5 is delivered to the apical membrane via Rab11a-mediated (R) endosomes, enhancing transapical fructose transport when luminal fructose levels are high. Intestine-specific deletion of Rab11a also inhibits SGLT1-mediated glucose transport, suggesting that this GTPase participates in the trafficking of transporters bound for the apical membrane. ❺ Portal fructose concentrations increase markedly with fructose intake. Figure modified from Reference . Abbreviations: ER, endoplasmic reticulum; GLUT, facilitative glucose transporter; KHK, ketohexokinase; Rab11a, Ras-related protein-in-brain 11a; SGLT1, Na⁺-dependent glucose transporter 1.

Figure 2

Major conformational states of GLUT5. Surface filling model of GLUT5, sectioned in the middle, in (a) outward-facing conformation (PDB ID 4YBQ) and (b) inward-facing conformation (PDB ID 4YB9). The N-terminal-half-six-helix domain is shown in cyan and the C-terminal-half-six-helix domain in magenta. The fructose binding site is in the central cavity. Binding of fructose in the outward-facing conformation promotes conformational change to the inward-facing conformation, and fructose is released into the cytoplasm. Abbreviations: GLUT, facilitative glucose transporter; PDB, Protein Data Bank.

Figure 3

Ligand recognition in GLUT2 and GLUT5. (a) In solution, hexoses adopt the pyranose, furanose, and open-chain forms. In crystal structures, three major conformers of glucose and fructose are observed (here are shown the conformers from PDB IDs 3KF3, 5GNY, and 2FA1). The bottom row shows a pairwise superposition among fructofuranose, glucopyranose, and fructopyranose. (b) Modeled glucose binding site of GLUT2 (on the basis of PDB IDs 4GBZ and 4ZW9) with β-glucopyranose. H-XI, -VII, -X, -IV are the transmembrane helices –11, –7, –10, and –4, respectively. The amino acid residues for the substrate binding site are conserved among GLUT1–4. (c) Modeled fructose (F) binding site of GLUT5 (PDB ID 4YBQ). Available crystal structures of GLUT5 do not include fructose, and the conformation of fructose is uncertain. (d) Surface filling model (sectioned in the middle) of GLUT5 liganded with MSNBA. (e) Putative binding site of MSNBA in GLUT5 model. Helices 4 and 5 are omitted for clarity. Abbreviations: GLUT, facilitative glucose transporter; MSNBA, N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine; PDB, Protein Data Bank.

Figure 4

Effect of peripheral blood fructose on blood glucose concentrations. Mice were fed isocaloric 20% glucose + 10% sucrose or 20% fructose + 10% sucrose diets under conditions of a reversed light cycle. Diets were removed at 2001 h (lights on) and returned at 0801 h (lights off) (data obtained from 102). After one week, mice were killed at 0800 h before feeding, and at 0900, 1030, 1200, and 1530 h during the dark phase; then blood sugar levels were analyzed. Peripheral blood glucose concentrations are plotted against blood fructose levels in wild-type mice (blue squares) and in KHK^−/− mice (red circles). Note that there are two abscissa lines because of the order-of-magnitude difference in range of blood fructose concentrations between mouse groups. Thus, for wild-type mice, peripheral glucose (5–25 mM) is plotted against peripheral fructose levels ranging from 0 to 0.4 mM (blue numbers), while, for KHK^−/− mice, peripheral glucose is plotted against fructose concentrations ranging from 0 to 6 mM (red number). It is quite clear that in wild-type mice, but not in KHK^−/− mice, large changes in blood glucose concentrations can be caused by small changes in blood fructose levels (102). Thus, chronic increases in blood fructose levels may eventually lead to hyperglycemia in humans and in animal models, each consuming high amounts of dietary fructose.