title: Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK.
abstract: Marked increases in fructose consumption have been tightly linked to metabolic diseases. One-third of ingested fructose is metabolized in the small intestine, but the underlying mechanisms regulating expression of fructose-metabolizing enzymes are not known. We used genetic mouse models to test the hypothesis that fructose absorption via glucose transporter protein, member 5 (GLUT5), metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein in brain 11a (Rab11a)-dependent endosomes are required for the regulation of intestinal fructolytic and gluconeogenic enzymes. Fructose feeding increased the intestinal mRNA and protein expression of these enzymes in the small intestine of adult wild-type (WT) mice compared with those gavage fed with lysine or glucose. Fructose did not increase expression of these enzymes in the GLUT5 knockout (KO) mice. Blocking intracellular fructose metabolism by KHK ablation also prevented fructose-induced upregulation. Glycolytic hexokinase I expression was similar between WT and GLUT5- or KHK-KO mice and did not vary with feeding solution. Gavage feeding with the fructose-specific metabolite glyceraldehyde did not increase enzyme expression, suggesting that signaling occurs before the hydrolysis of fructose to three-carbon compounds. Impeding GLUT5 trafficking to the apical membrane using intestinal epithelial cell-specific Rab11a-KO mice impaired fructose-induced upregulation. KHK expression was uniformly distributed along the villus but was localized mainly in the basal region of the cytosol of enterocytes. The feedforward upregulation of fructolytic and gluconeogenic enzymes specifically requires GLUT5 and KHK and may proactively enhance the intestine's ability to process anticipated increases in dietary fructose concentrations.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and.
authors.forename: Chirag
authors.initials: C
authors.lastname: Patel
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and.
authors.forename: Veronique
authors.initials: V
authors.lastname: Douard
authors.affiliation: Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Shiyan
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and.
authors.forename: Phuntila
authors.initials: P
authors.lastname: Tharabenjasin
authors.affiliation: Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and ferraris@njms.rutgers.edu.
authors.forename: Ronaldo P
authors.initials: RP
authors.lastname: Ferraris
mesh_terms: D000818:Animals; D004040:Dietary Carbohydrates / Q000378:metabolism*; D020895:Enterocytes / Q000201:enzymology*; D005631:Fructokinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis / Q000235:genetics; D051246:Glucose Transport Proteins, Facilitative / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051296:Glucose Transporter Type 5; D006868:Hydrolysis; D007421:Intestine, Small / Q000201:enzymology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D004040:Dietary Carbohydrates; D005631:Fructokinases; D005632:Fructose; D051246:Glucose Transport Proteins, Facilitative; D051296:Glucose Transporter Type 5; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C465351:Slc2a5 protein, mouse; C021475:ketohexokinase
keywords: Ras-related protein in brain 11a; fructolysis; gluconeogenesis; glucose transporter protein, member 5; glyceraldehyde; ketohexokinase; mice; small intestine