**4.8. GLUT5** *(SLC2A5)*

Human GLUT5 was initially cloned from an intestinal epithelial cell line. GLUT5 is considered as the prototypic fructose transporter – when expressed in *Xenopus laevis* oocytes the human protein transports fructose with a Km of 6 mM without any noticeable glucose transport activity. However, fructose transport is not inhibited by cytochalasin B, phlore‐ tin or phlorizin. Besides fructose, the rat GLUT5 transports glucose, an activity that can be blocked by cytochalasin B. In humans, rats and mice, GLUT5 is primarily expressed in the jejunal region of the small intestine. Lower levels of the protein are expressed in the kidney, the brain, skeletal muscle, and adipose tissue. GLUT5 mediates fructose absorption in the jejunum at the apical, and potentially, at the basolateral membrane, of the epithelial cells into the portal vein (Figure 3B).

#### *4.8.1. GLUT5 physiology*

## *Mouse Models of GLUT5 deficiency*

GLUT5 deficiency is associated with reduced fructose absorption when animals are challenged by a high fructose diet. While wildtype mice upon high fructose feeding display an enhanced salt absorption in their jejuna and develop systemic hypertension, GLUT5 knockout mice do not show fructose stimulated salt absorption. Instead, the animals display impaired nutrient absorption that is accompanied by hypotension. Absence of GLUT5 leads to a massive dilatation of the cecum and colon, consistent with severe malabsorption. On a normal chow diet, GLUT5 deficient mice have normal blood pressure and display normal weight gain. The phenotype of GLUT5 deficient mice demonstrates that this isoform is essential for fructose absorption by the intestine and thereby fundamentally involved in fructose induced hyper‐ tension.

#### **4.9. GLUT7** *(SLC2A7)*

The human GLUT7 was cloned from an intestinal cDNA library using a PCR-based strategy. GLUT7 is primarily expressed in the small intestine and colon, although mRNA has been detected in the testes and prostate as well. The protein has been localized to the apical membrane of the small intestine and colon. GLUT7 shows a rather high affinity for glucose and fructose (*K*m for glucose=0.3mM) while galactose, 2-DG, and xylose are not transported. Sugar transport by GLUT7 is not inhibited by cytochalasin B or phloretin. Sequence alignments between fructose and non-fructose transporting GLUT isoforms identified a motif in GLUT7 that potentially confers its ability to transport fructose. Mutational analysis of those residues in GLUT7 identified isoleucine 314 as an important determinant for fructose affinity. The finding of a specific residue within the extracellular vestibule of helix 7 that drives substrate specificity was extended to GLUT2, 5, 9 and 11 and proposed as a common NXI/V consensus motif among isoforms capable of transporting fructose.
