title: Protein kinases, TNF-{alpha}, and proteasome contribute in the inhibition of fructose intestinal transport by sepsis in vivo.
abstract: Lipopolysaccharide (LPS) endotoxin is a causative agent of sepsis. The aim of this study was to examine LPS effects on intestinal fructose absorption and to decipher mechanisms. Sepsis was induced by intravenous injection of LPS in rabbits. The ultrastructural study and DNA fragmentation patterns were identical in the intestine of LPS and sham animals. LPS treatment reduced fructose absorption altering both mucosal-to-serosal transepithelial fluxes and uptake into brush border membrane vesicles (BBMVs). Cytochalasin B was ineffective on fructose uptake, indicating that GLUT5, but not GLUT2, transport activity was targeted. GLUT5 protein levels in BBMvs were lower in LPS than in sham-injected rabbits. Thus lower fructose transport resulted from lower levels of GLUT5 protein. LPS treatment decreased GLUT5 levels by proteasome-dependent degradation. Specific inhibitors of PKC, PKA, and MAP kinases (p38MAPK, JNK, MEK1/2) protected fructose uptake from adverse LPS effect. Moreover, a TNF-alpha antagonist blocked LPS action on fructose uptake. We conclude that intestinal fructose transport inhibition by LPS is associated with diminished GLUT5 numbers in the brush border membrane of enterocytes triggered by activation of several interrelated signaling cascades and proteasome degradation.
authors.affiliation: Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: García-Herrera
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Marca
authors.forename: Edith
authors.initials: E
authors.lastname: Brot-Laroche
authors.forename: Natalia
authors.initials: N
authors.lastname: Guillén
authors.forename: Sergio
authors.initials: S
authors.lastname: Acin
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Navarro
authors.forename: Jesús
authors.initials: J
authors.lastname: Osada
authors.forename: M Jesús
authors.initials: MJ
authors.lastname: Rodríguez-Yoldi
mesh_terms: D000818:Animals; D017209:Apoptosis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D015536:Down-Regulation; D020895:Enterocytes / Q000378:metabolism; D005632:Fructose / Q000378:metabolism*; D051296:Glucose Transporter Type 5 / Q000378:metabolism*; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008871:Microvilli / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D018805:Sepsis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051296:Glucose Transporter Type 5; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D005632:Fructose; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex