Transport, metabolism, and endosomal trafficking‐dependent regulation of intestinal fructose absorption

Abstract

Dietary fructose that is linked to metabolic abnormalities can up-regulate its own absorption, but the underlying regulatory mechanisms are not known. We hypothesized that glucose transporter (GLUT) protein, member 5 (GLUT5) is the primary fructose transporter and that fructose absorption via GLUT5, metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein-in-brain 11 (Rab11)a-dependent endosomes are each required for regulation. Introducing fructose but not lysine and glucose solutions into the lumen increased by 2- to 10-fold the heterogeneous nuclear RNA, mRNA, protein, and activity levels of GLUT5 in adult wild-type mice consuming chow. Levels of GLUT5 were >100-fold that of candidate apical fructose transporters GLUTs 7, 8, and 12 whose expression, and that of GLUT 2 and the sodium-dependent glucose transporter protein 1 (SGLT1), was not regulated by luminal fructose. GLUT5-knockout (KO) mice exhibited no facilitative fructose transport and no compensatory increases in activity and expression of SGLT1 and other GLUTs. Fructose could not up-regulate GLUT5 in GLUT5-KO, KHK-KO, and intestinal epithelial cell-specific Rab11a-KO mice. The fructose-specific metabolite glyceraldehyde did not increase GLUT5 expression. GLUT5 is the primary transporter responsible for facilitative absorption of fructose, and its regulation specifically requires fructose uptake and metabolism and normal GLUT5 trafficking to the apical membrane.

Fructose metabolism and metabolic disease

“…GLUT5 is highly expressed on enterocytes' luminal membrane and is also expressed basolaterally (28). Deletion of Glut5 in mice reduces fructose absorption by 75% and causes cecum and colon dilatation as well as gas accumulation (29).…”

Identification of essential amino acids for glucose transporter 5 (GLUT5)-mediated fructose transport

“…Although other members of the GLUT family (e.g. GLUT7, GLUT8 and GLUT12) are present in the small intestine, their expression level and contribution to overall fructose transport seems to be of minor importance [2][3][4]. The involvement of GLUT5 in the pathophysiology of fructose malabsorption is a matter of debate.…”

IFN‐γ/mTORC1 decreased Rab11 in Schwann cells of diabetic peripheral neuropathy, inhibiting cell proliferation via GLUT1 downregulation

“…GLUT, also known as solute carrier family, was the key receptor to regulate glucose uptake and metabolism (Deng & Yan, 2016). Again, GLUTs were located in PM and affected by the recycling endosome system (Patel, Douard, Yu, Gao, & Ferraris, 2015). We found in this study that Rab11 knockdown decreased GLUT1 expression in RSC96 cells, especially in the PM.…”