The Experts below are selected from a list of 23836188 Experts worldwide ranked by ideXlab platform
Kelle H Moley - One of the best experts on this subject based on the ideXlab platform.
-
glucose transporter 8 glut8 mediates fructose induced de novo lipogenesis and macrosteatosis
Journal of Biological Chemistry, 2014Co-Authors: Brian J Debosch, Zhouji Chen, Jessica Saben, Brian N Finck, Kelle H MoleyAbstract:Abstract ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and it is thought to be the hepatic manifestation of the metabolic syndrome. Excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans, but the pathogenic mechanisms of fructose induced metabolic syndrome and NAFLD are poorly understood. GLUT8 (Slc2A8) is a facilitative glucose and fructose transporter that is highly expressed in liver, heart and other oxidative tissues. We previously demonstrated that female mice lacking GLUT8 exhibit impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, is in part mediated by GLUT8. Here, we tested the hypothesis that GLUT8 is required for hepatocyte fructose uptake and for the development of fructose induced NAFLD. We demonstrate that GLUT8 is a cell surface localized transporter, and that GLUT8 overexpression or GLUT8 shRNA mediated gene silencing significantly induces and blocks radiolabeled fructose uptake in cultured hepatocytes. We further show diminished fructose uptake and de novo lipogenesis in fructose-challenged GLUT8 deficient hepatocytes. Finally, livers from longterm high fructose diet fed GLUT8 deficient mice exhibited attenuated fructose induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin stimulated Akt phosphorylation. GLUT8 is thus essential for hepatocyte fructose transport and fructose induced macrosteatosis. Fructose delivery across the hepatocyte membrane is thus a proximal, modifiable disease mechanism that may be exploited to prevent NAFLD.
-
glucose transporter 8 glut8 mediates fructose induced de novo lipogenesis and macrosteatosis
Journal of Biological Chemistry, 2014Co-Authors: Brian J Debosch, Zhouji Chen, Jessica Saben, Brian N Finck, Kelle H MoleyAbstract:Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and it is thought to be the hepatic manifestation of the metabolic syndrome. Excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans, but the pathogenic mechanisms of fructose-induced metabolic syndrome and NAFLD are poorly understood. GLUT8 (Slc2A8) is a facilitative glucose and fructose transporter that is highly expressed in liver, heart, and other oxidative tissues. We previously demonstrated that female mice lacking GLUT8 exhibit impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, is in part mediated by GLUT8. Here, we tested the hypothesis that GLUT8 is required for hepatocyte fructose uptake and for the development of fructose-induced NAFLD. We demonstrate that GLUT8 is a cell surface-localized transporter and that GLUT8 overexpression or GLUT8 shRNA-mediated gene silencing significantly induces and blocks radiolabeled fructose uptake in cultured hepatocytes. We further show diminished fructose uptake and de novo lipogenesis in fructose-challenged GLUT8-deficient hepatocytes. Finally, livers from long term high-fructose diet-fed GLUT8-deficient mice exhibited attenuated fructose-induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin-stimulated Akt phosphorylation. GLUT8 is thus essential for hepatocyte fructose transport and fructose-induced macrosteatosis. Fructose delivery across the hepatocyte membrane is thus a proximal, modifiable disease mechanism that may be exploited to prevent NAFLD. Background: GLUT8 is a facilitative fructose and glucose transporter expressed in liver. Results: GLUT8-deficient mice are resistant to fructose-induced fatty liver disease. Conclusion: Hexose transporters can mediate fructose-induced fatty liver disease. Significance: Hepatic hexose transporters represent a novel class of targets to prevent or modulate non-alcoholic fatty liver disease.
-
glucose transporter 8 glut8 regulates enterocyte fructose transport and global mammalian fructose utilization
Endocrinology, 2012Co-Authors: Brian J Debosch, Kelle H MoleyAbstract: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 [14C]-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.
Brian J Debosch - One of the best experts on this subject based on the ideXlab platform.
-
Tissue-Specific Fructose Metabolism in Obesity and Diabetes.
Current diabetes reports, 2020Co-Authors: Robert N. Helsley, Brian J Debosch, Francois Moreau, Manoj K. Gupta, Aurelia Radulescu, Samir SofticAbstract:Purpose of review The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). Recent findings Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake. Since inhibitors targeting fructose metabolism are being developed for the management of NAFLD and diabetes, it is essential to recognize how inability of one tissue to metabolize fructose may affect metabolism in the other tissues. The primary sites of fructose metabolism are the liver, intestine, and kidney. Skeletal muscle and adipose tissue can also metabolize a large portion of fructose load, especially in the setting of ketohexokinase deficiency, the rate-limiting enzyme of fructose metabolism. Fructose can also be sensed by the pancreas and the brain, where it can influence essential functions involved in energy homeostasis. Lastly, fructose is metabolized by the testes, red blood cells, and lens of the eye where it may contribute to infertility, advanced glycation end products, and cataracts, respectively. An increase in sugar intake, particularly fructose, has been associated with the development of obesity and its complications. Inhibition of fructose utilization in tissues primary responsible for its metabolism alters consumption in other tissues, which have not been traditionally regarded as important depots of fructose metabolism.
-
glucose transporter 8 glut8 mediates fructose induced de novo lipogenesis and macrosteatosis
Journal of Biological Chemistry, 2014Co-Authors: Brian J Debosch, Zhouji Chen, Jessica Saben, Brian N Finck, Kelle H MoleyAbstract:Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and it is thought to be the hepatic manifestation of the metabolic syndrome. Excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans, but the pathogenic mechanisms of fructose-induced metabolic syndrome and NAFLD are poorly understood. GLUT8 (Slc2A8) is a facilitative glucose and fructose transporter that is highly expressed in liver, heart, and other oxidative tissues. We previously demonstrated that female mice lacking GLUT8 exhibit impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, is in part mediated by GLUT8. Here, we tested the hypothesis that GLUT8 is required for hepatocyte fructose uptake and for the development of fructose-induced NAFLD. We demonstrate that GLUT8 is a cell surface-localized transporter and that GLUT8 overexpression or GLUT8 shRNA-mediated gene silencing significantly induces and blocks radiolabeled fructose uptake in cultured hepatocytes. We further show diminished fructose uptake and de novo lipogenesis in fructose-challenged GLUT8-deficient hepatocytes. Finally, livers from long term high-fructose diet-fed GLUT8-deficient mice exhibited attenuated fructose-induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin-stimulated Akt phosphorylation. GLUT8 is thus essential for hepatocyte fructose transport and fructose-induced macrosteatosis. Fructose delivery across the hepatocyte membrane is thus a proximal, modifiable disease mechanism that may be exploited to prevent NAFLD. Background: GLUT8 is a facilitative fructose and glucose transporter expressed in liver. Results: GLUT8-deficient mice are resistant to fructose-induced fatty liver disease. Conclusion: Hexose transporters can mediate fructose-induced fatty liver disease. Significance: Hepatic hexose transporters represent a novel class of targets to prevent or modulate non-alcoholic fatty liver disease.
-
glucose transporter 8 glut8 mediates fructose induced de novo lipogenesis and macrosteatosis
Journal of Biological Chemistry, 2014Co-Authors: Brian J Debosch, Zhouji Chen, Jessica Saben, Brian N Finck, Kelle H MoleyAbstract:Abstract ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and it is thought to be the hepatic manifestation of the metabolic syndrome. Excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans, but the pathogenic mechanisms of fructose induced metabolic syndrome and NAFLD are poorly understood. GLUT8 (Slc2A8) is a facilitative glucose and fructose transporter that is highly expressed in liver, heart and other oxidative tissues. We previously demonstrated that female mice lacking GLUT8 exhibit impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, is in part mediated by GLUT8. Here, we tested the hypothesis that GLUT8 is required for hepatocyte fructose uptake and for the development of fructose induced NAFLD. We demonstrate that GLUT8 is a cell surface localized transporter, and that GLUT8 overexpression or GLUT8 shRNA mediated gene silencing significantly induces and blocks radiolabeled fructose uptake in cultured hepatocytes. We further show diminished fructose uptake and de novo lipogenesis in fructose-challenged GLUT8 deficient hepatocytes. Finally, livers from longterm high fructose diet fed GLUT8 deficient mice exhibited attenuated fructose induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin stimulated Akt phosphorylation. GLUT8 is thus essential for hepatocyte fructose transport and fructose induced macrosteatosis. Fructose delivery across the hepatocyte membrane is thus a proximal, modifiable disease mechanism that may be exploited to prevent NAFLD.
-
glucose transporter 8 glut8 regulates enterocyte fructose transport and global mammalian fructose utilization
Endocrinology, 2012Co-Authors: Brian J Debosch, Kelle H MoleyAbstract: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 [14C]-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.
Shunsuke Furuyama - One of the best experts on this subject based on the ideXlab platform.
-
ribose 1 5 bisphosphate is a putative regulator of fructose 6 phosphate fructose 1 6 bisphosphate cycle in liver
The International Journal of Biochemistry & Cell Biology, 2000Co-Authors: Masaru Sawada, Yuka Mitsui, Hiroshi Sugiya, Shunsuke FuruyamaAbstract:Abstract 6-Phosphofructo-1-kinase and fructose-1,6-bisphosphatase are rate-limiting enzymes for glycolysis and gluconeogenesis respectively, in the fructose 6-phosphate/fructose 1,6-bisphosphate cycle in the liver. The effect of ribose 1,5-bisphosphate on the enzymes was investigated. Ribose 1,5-bisphosphate synergistically relieved the ATP inhibition and increased the affinity of liver 6-phosphofructo-1-kinase for fructose 6-phosphate in the presence of AMP. Ribose 1,5-bisphosphate synergistically inhibited fructose-1,6-bisphosphatase in the presence of AMP. The activating effect on 6-phosphofructo-1-kinase and the inhibitory effect on fructose-1,6-bisphosphatase suggest ribose 1,5-bisphosphate is a potent regulator of the fructose 6-phosphate/fructose 1,6-bisphosphate cycle in the liver.
Charles F Zorumski - One of the best experts on this subject based on the ideXlab platform.
-
effects of fructose 1 6 bisphosphate on morphological and functional neuronal integrity in rat hippocampal slices during energy deprivation
Neuroscience, 2003Co-Authors: Yukitoshi Izumi, Ann Benz, Hiroshi Katsuki, Mio Matsukawa, David B Clifford, Charles F ZorumskiAbstract:Abstract d- Fructose-1,6-bisphosphate, a high energy glycolytic intermediate, attenuates ischemic damage in a variety of tissues, including brain. To determine whether d- fructose-1,6-bisphosphate serves as an alternate energy substrate in the CNS, rat hippocampal slices were treated with d- fructose-1,6-bisphosphate during glucose deprivation. Unlike pyruvate, an endproduct of glycolysis, 10 mM d- fructose-1,6-bisphosphate did not preserve synaptic transmission or morphological integrity of CA1 pyramidal neurons during glucose deprivation. Moreover, during glucose deprivation, 10-mM d- fructose-1,6-bisphosphate failed to maintain adenosine triphosphate levels in slices. d- Fructose-1,6-bisphosphate, however, attenuated acute neuronal degeneration produced by 200 μM iodoacetate, an inhibitor of glycolysis downstream of d- fructose-1,6-bisphosphate. Because (5 S , 10 R )-(+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine, an antagonist of N -methyl- d- aspartate receptors, exhibited similar protection against iodoacetate damage, we examined whether (5 S , 10 R )-(+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine and d- fructose-1,6-bisphosphate share a common neuroprotective mechanism. Indeed, d- fructose-1,6-bisphosphate diminished N -methyl- d- aspartate receptor-mediated synaptic responses and partially attenuated neuronal degeneration induced by 100-μM N -methyl- d- aspartate. Taken together, these results indicate that d- fructose-1,6-bisphosphate is unlikely to serve as an energy substrate in the hippocampus, and that neuroprotective effects of d- fructose-1,6-bisphosphate are mediated by mechanisms other than anaerobic energy supply.
Peter Schonheit - One of the best experts on this subject based on the ideXlab platform.
-
fructose degradation in the haloarchaeon haloferax volcanii involves a bacterial type phosphoenolpyruvate dependent phosphotransferase system fructose 1 phosphate kinase and class ii fructose 1 6 bisphosphate aldolase
Journal of Bacteriology, 2012Co-Authors: Andreas Pickl, Ulrike Johnsen, Peter SchonheitAbstract:The halophilic archaeon Haloferax volcanii utilizes fructose as a sole carbon and energy source. Genes and enzymes involved in fructose uptake and degradation were identified by transcriptional analyses, deletion mutant experiments, and enzyme characterization. During growth on fructose, the gene cluster HVO_1495 to HVO_1499, encoding homologs of the five bacterial phosphotransferase system (PTS) components enzyme IIB (EIIB), enzyme I (EI), histidine protein (HPr), EIIA, and EIIC, was highly upregulated as a cotranscript. The in-frame deletion of HVO_1499, designated ptfC (ptf stands for phosphotransferase system for fructose) and encoding the putative fructose-specific membrane component EIIC, resulted in a loss of growth on fructose, which could be recovered by complementation in trans. Transcripts of HVO_1500 (pfkB) and HVO_1494 (fba), encoding putative fructose-1-phosphate kinase (1-PFK) and fructose-1,6-bisphosphate aldolase (FBA), respectively, as well as 1-PFK and FBA activities were specifically upregulated in fructose-grown cells. pfkB and fba knockout mutants did not grow on fructose, whereas growth on glucose was not inhibited, indicating the functional involvement of both enzymes in fructose catabolism. Recombinant 1-PFK and FBA obtained after homologous overexpression were characterized as having kinetic properties indicative of functional 1-PFK and a class II type FBA. From these data, we conclude that fructose uptake in H. volcanii involves a fructose-specific PTS generating fructose-1-phosphate, which is further converted via fructose-1,6-bisphosphate to triose phosphates by 1-PFK and FBA. This is the first report of the functional involvement of a bacterial-like PTS and of class II FBA in the sugar metabolism of archaea.
-
different glycolytic pathways for glucose and fructose in the halophilic archaeon halococcus saccharolyticus
Archives of Microbiology, 2001Co-Authors: Ulrike Johnsen, Martina Selig, Karina B Xavier, H Santos, Peter SchonheitAbstract:The glucose and fructose degradation pathways were analyzed in the halophilic archaeon Halococcus saccharolyticus by 13C-NMR labeling studies in growing cultures, comparative enzyme measurements and cell suspension experiments. H. saccharolyticus grown on complex media containing glucose or fructose specifically 13C-labeled at C1 and C3, formed acetate and small amounts of lactate. The 13C-labeling patterns, analyzed by 1H- and 13C-NMR, indicated that glucose was degraded via an Entner-Doudoroff (ED) type pathway (100%), whereas fructose was degraded almost completely via an Embden-Meyerhof (EM) type pathway (96%) and only to a small extent (4%) via an ED pathway. Glucose-grown and fructose-grown cells contained all the enzyme activities of the modified versions of the ED and EM pathways recently proposed for halophilic archaea. Glucose-grown cells showed increased activities of the ED enzymes gluconate dehydratase and 2-keto-3-deoxy-gluconate kinase, whereas fructose-grown cells contained higher activities of the key enzymes of a modified EM pathway, ketohexokinase and fructose-1-phosphate kinase. During growth of H. saccharolyticus on media containing both glucose and fructose, diauxic growth kinetics were observed. After complete consumption of glucose, fructose was degraded after a lag phase, in which fructose-1-phosphate kinase activity increased. Suspensions of glucose-grown cells consumed initially only glucose rather than fructose, those of fructose-grown cells degraded fructose rather than glucose. Upon longer incubation times, glucose- and fructose-grown cells also metabolized the alternate hexoses. The data indicate that, in the archaeon H. saccharolyticus, the isomeric hexoses glucose and fructose are degraded via inducible, functionally separated glycolytic pathways: glucose via a modified ED pathway, and fructose via a modified EM pathway.
