title: Glucose transporter 8 (GLUT8) regulates enterocyte fructose transport and global mammalian fructose utilization.
abstract: Enterocyte fructose absorption is a tightly regulated process that precedes the deleterious effects of excess dietary fructose in mammals. Glucose transporter (GLUT)8 is a glucose/fructose transporter previously shown to be expressed in murine intestine. The in vivo function of GLUT8, however, remains unclear. Here, we demonstrate enhanced fructose-induced fructose transport in both in vitro and in vivo models of enterocyte GLUT8 deficiency. Fructose exposure stimulated [(14)C]-fructose uptake and decreased GLUT8 protein abundance in Caco2 colonocytes, whereas direct short hairpin RNA-mediated GLUT8 knockdown also stimulated fructose uptake. To assess GLUT8 function in vivo, we generated GLUT8-deficient (GLUT8KO) mice. GLUT8KO mice exhibited significantly greater jejunal fructose uptake at baseline and after high-fructose diet (HFrD) feeding vs. wild-type mice. Strikingly, long-term HFrD feeding in GLUT8KO mice exacerbated fructose-induced increases in blood pressure, serum insulin, low-density lipoprotein and total cholesterol vs. wild-type controls. Enhanced fructose uptake paralleled with increased abundance of the fructose and glucose transporter, GLUT12, in HFrD-fed GLUT8KO mouse enterocytes and in Caco2 cultures exposed to high-fructose medium. We conclude that GLUT8 regulates enterocyte fructose transport by regulating GLUT12, and that disrupted GLUT8 function has deleterious long-term metabolic sequelae. GLUT8 may thus represent a modifiable target in the prevention and treatment of malnutrition or the metabolic syndrome.
authors: Department of Pediatrics, Washington University in St. Louis School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
authors: Brian J
authors: BJ
authors: DeBosch
authors: Maggie
authors: M
authors: Chi
authors: Kelle H
authors: KH
authors: Moley
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005632:Fructose / Q000378:metabolism* / Q000494:pharmacology*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C405325:SLC2A8 protein, human; C498628:Slc2a8 protein, mouse; D005632:Fructose