Fructose the odd man out. Why is the genomic control of intestinal GLUT5 expression different?

The expression of hexose transporters in the small intestine is essential for many animals to obtain a significant component of their energy supply. Neonatal mammals obtain their carbohydrate in the form of lactose (milk sugar), which is comprised of glucose and galactose, meaning that they do not normally see any dietary fructose until weaning. Surprisingly, even though these are the only three common dietary hexoses, several transporter proteins are involved in their transfer from the intestinal lumen to the portal blood. The best known of these is the sodium-coupled sugar transporter (SGLT1, SLC5A1), which couples the electrochemical gradient of two sodium ions to a single glucose or galactose molecule, thus enabling an almost complete removal of these hexoses from the meal (Wright et al. 2007). This would suggest that SGLT1 would be the only transporter needed by mammalian neonates in order to move the dietary carbohydrate into the epithelial cells (enterocytes). Exit from the enterocytes into the blood stream is then mediated by the facilitated hexose transporter GLUT2 (SLC2A2), which can handle all three hexoses with low affinity and high capacity (Cheeseman, 1993). During weaning fructose will start to appear in the diet for the first time and as SGLT1 cannot handle this hexose another route of uptake needs to be expressed. This is achieved by the facilitated transporter GLUT5 and by the transient expression of GLUT2 in the apical membrane (Kellett et al. 2008). It has been known for a long time that the expression of hexose transporters is highly dependent upon the dietary composition, which suggests that there are response elements that detect the levels of carbohydrate or specific hexoses in the intestinal lumen. In the mature animal GLUT5 expression is uniquely regulated by the presence of fructose in the diet (Inukai et al. 1993), while SGLT1 and GLUT2 are influenced by all three hexoses (Miyamoto et al. 1993). These effects appear to result from alterations in the rate of transcription, i.e. genomic control. In the case of SGLT1 and GLUT2, their expression is programmed at the time of birth of the enterocytes in the crypts surrounding the base of the intestinal villi. Thus, the time course for changes in expression of these transporters is a function of the life span of the continually renewed epithelium (3–5 days). However, the GLUT5 response appears to occur in the enterocytes on the villi and may be much faster (Ferraris, 2001). Also, it should be noted that unlike almost all other tissues, which need to protect themselves against excessive hexose exposure, the intestine responds to match its transport capacity for hexoses to their content in the diet. In this issue of The Journal of Physiology, Douard et al. (2008) have attempted to determine how the initial expression of GLUT5 in the neonatal intestine is controlled. Is it hard wired, i.e. determined in a pre-programmed manner such that time alone is the determining factor or can the appearance of fructose in the diet mediate a precocious appearance of the protein? Dr Ferraris' group have previously shown that the introduction of fructose in the diet can induce GLUT5 expression after 14 days of age and no sooner, unless the glucocorticoid/mineralocorticoid agonist dexamethasone is administered to prime the system. Again, in the rat this effect is limited to a narrow time window of 10–14 days of age. Dexamethasone has long been known to be able to induce precocious maturation of the small intestine, increasing the expression of both digestive enzymes associated with the epithelial cells and transporter proteins. However, as Douard et al. (2008) point out, the mechanism of action of this synthetic hormone on the intestine is unknown. They have asked the question is the action mediated at the genomic level or at a control point further downstream? Using an ingenious series of experiments they have demonstrated that dexamethasone mediates its effects through a glucocorticoid receptor pathway, but this alone does not induce GLUT5 expression. Instead, it appears that the hormone signals the expression of another protein(s), as yet unidentified, which then allows for the luminal presence of fructose to initiate transcription of the SLC2A5 gene. They postulate that dexamethasone is mimicking the glucocorticoid surge that occurs during development, but more importantly, by taking advantage of the developmental changes that occur prior to weaning, they have been able to identify a potential cluster of genes that are involved in fructose sensing by the small intestine. This work may well have important implications for our understanding of how the absorption of dietary hexoses is controlled and in particular those for fructose. It has become apparent over the last few years that the addition of fructose to many foodstuffs as a dietary supplement may be contributing to the increasing incidence of juvenile obesity and diabetes which the Western world is currently facing. Hopefully, a better understanding of the physiological control of the absorption of this hexose may lead to appropriate strategies to mitigate this significant problem.

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