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 ϳ75% in the jejunum and decreased the concentration of serum fructose by ϳ90% 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.

Glucose sensing and signalling; regulation of intestinal glucose transport

“…The presence of apical GLUT2 should enable fructose absorption when GLUT5 activity is limiting; however, GLUT5 knockout mice cannot absorb fructose, even when their intestine is infused with high concentrations of glucose or fructose (33) . In addition, immunohistochemistry using two different antibodies raised against peptides corresponding to the C-terminal region, or to residues 40-55 of the GLUT2 amino acid sequence has demonstrated that the GLUT2 protein is exclusively located on the basolateral membrane of enterocytes (23)(24)(25) .…”

Fructose‐induced symptoms beyond malabsorption in FGID

“…11,12 Recent human data from infant 13,14 and diabetic 15 studies have supported this, where a reduced expression of GLUT5 were associated with high rates of fructose malabsorption. Moreover, fructose malabsorption is not associated with GLUT2 or GLUT5 mutations.…”

Intestinal fructose transport and malabsorption in humans

“…The importance of GLUT5 in fructose absorption has been investigated further in a GLUT5 knockout mouse model (2). In these GLUT5 knockout mice fructose absorption was decreased by 75% in the jejunum and the concentration of serum fructose was decreased by 90%, compared with wild-type mice.…”

“…Recently, a GLUT5 knockout mouse model was shown to exhibit decreased absorption of dietary fructose, with consequent distension of the large intestine with fluid and gas. The model was described as having the hallmarks of profound fructose malabsorption (2). With this and other advances in the understanding of fructose transport, it may become possible to characterize a mechanism for fructose malabsorption in humans.…”