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Socha-Banasiak A, Sakowicz A, Gaj Z, Kolejwa M, Gach A, Czkwianianc E. Intestinal fructose transporters GLUT5 and GLUT2 in children and adolescents with obesity and metabolic disorders. Adv Med Sci 2024; 69:349-355. [PMID: 39059468 DOI: 10.1016/j.advms.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/19/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
PURPOSE The excessive fructose intake including high-fructose corn syrup (HFCS) may be responsible for increase of obesity occurrence. This study was designed to find potential differences in duodenal fructose transporters on mRNA and protein levels between obese and normal weight children and adolescents. MATERIALS/METHODS We performed a cross-sectional study on a group of 106 hospitalized patients aged 12 to 18. Glucose transporter 2 (GLUT2) and glucose transporter 5 (GLUT5) mRNA as well as protein levels (ELISA and Western blot methods) were assessed in duodenal mucosa biopsies of the patients categorized as obese or normal weight. Additionally, the expression of the aforementioned transporters was analyzed in patients based on the presence of insulin resistance (IR) and metabolic syndrome (MS). RESULTS In children with obesity, increased duodenal protein levels of GLUT5 (Relative protein GLUT5 expression/ACTB) (0.027 ± 0.009 vs. 0.011 ± 0.006, p < 0.05) but not GLUT2 as compared with the normal weight group, were revealed. No significant differences in duodenal relative GLUT2 and GLUT5 genes expression between the studied groups were found. There was no relationship between the presence of IR or MS and intestinal mRNA GLUT2 and GLUT5 as well as GLUT2 protein expression. CONCLUSION The upregulation of the duodenal GLUT5 may contribute to obesity occurrence in children and adolescents.
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Affiliation(s)
- Anna Socha-Banasiak
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland.
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland
| | - Zuzanna Gaj
- Center of Medical Laboratory Diagnostics and Screening, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
| | - Michał Kolejwa
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
| | - Agnieszka Gach
- Department of Genetics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
| | - Elżbieta Czkwianianc
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
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Staltner R, Burger K, Baumann A, Bergheim I. Fructose: a modulator of intestinal barrier function and hepatic health? Eur J Nutr 2023; 62:3113-3124. [PMID: 37596353 PMCID: PMC10611622 DOI: 10.1007/s00394-023-03232-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/04/2023] [Indexed: 08/20/2023]
Abstract
PURPOSE Consumption of fructose has repeatedly been discussed to be a key factor in the development of health disturbances such as hypertension, diabetes type 2, and non-alcoholic fatty liver disease. Despite intense research efforts, the question if and how high dietary fructose intake interferes with human health has not yet been fully answered. RESULTS Studies suggest that besides its insulin-independent metabolism dietary fructose may also impact intestinal homeostasis and barrier function. Indeed, it has been suggested by the results of human and animal as well as in vitro studies that fructose enriched diets may alter intestinal microbiota composition. Furthermore, studies have also shown that both acute and chronic intake of fructose may lead to an increased formation of nitric oxide and a loss of tight junction proteins in small intestinal tissue. These alterations have been related to an increased translocation of pathogen-associated molecular patterns (PAMPs) like bacterial endotoxin and an induction of dependent signaling cascades in the liver but also other tissues. CONCLUSION In the present narrative review, results of studies assessing the effects of fructose on intestinal barrier function and their impact on the development of health disturbances with a particular focus on the liver are summarized and discussed.
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Affiliation(s)
- Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2, A-1090, Vienna, Austria
| | - Katharina Burger
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2, A-1090, Vienna, Austria
| | - Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2, A-1090, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2, A-1090, Vienna, Austria.
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Fiorentino TV, De Vito F, Suraci E, Marasco R, Hribal ML, Luzza F, Sesti G. Obesity and overweight are linked to increased sodium-glucose cotransporter 1 and glucose transporter 5 levels in duodenum. Obesity (Silver Spring) 2023; 31:724-731. [PMID: 36746764 DOI: 10.1002/oby.23653] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/03/2022] [Accepted: 10/23/2022] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Prior evidence indicates that individuals with obesity have an accelerated intestinal glucose absorption. This cross-sectional study evaluated whether those with overweight or obesity display higher duodenal protein levels of the glucose carriers sodium-glucose cotransporter 1 (SGLT-1), glucose transporter 2 (GLUT-2), and glucose transporter 5 (GLUT-5). METHODS SGLT-1, GLUT-2, and GLUT-5 protein levels were assessed on duodenal mucosa biopsies of 52 individuals without diabetes categorized on the basis of their BMI as lean, with overweight, or with obesity. RESULTS Individuals with overweight and obesity exhibited progressively increased duodenal protein levels of SGLT-1 and GLUT-5 as compared with the lean group. Conversely, no differences in duodenal GLUT-2 abundance were found among the three groups. Univariate analysis showed that SGLT-1 and GLUT-5 protein levels were positively correlated with BMI, waist circumference, 1-hour post-load glucose, fasting and post-load insulin, and insulin secretion and resistance levels. Furthermore, a positive relationship was detected between intestinal GLUT-5 levels and serum uric acid concentrations, a product of fructose metabolism known to be involved in the pathogenesis of obesity and its complications. CONCLUSIONS Individuals with overweight and obesity display enhanced duodenal SGLT-1 and GLUT-5 abundance, which correlates with increased postprandial glucose concentrations, insulin resistance, and hyperinsulinemia.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Francesca De Vito
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Evelina Suraci
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Raffaella Marasco
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Marta Letizia Hribal
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Rome, Italy
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Abstract
The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases.
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Affiliation(s)
- Sunhee Jung
- Department of Biological Chemistry, University of California, Irvine, California, USA
| | - Hosung Bae
- Department of Biological Chemistry, University of California, Irvine, California, USA
| | - Won-Suk Song
- Department of Biological Chemistry, University of California, Irvine, California, USA;,Institute of Bioengineering, Bio-MAX, Seoul National University, Seoul, South Korea
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California, Irvine, California, USA;,Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA,Center for Complex Biological Systems, University of California, Irvine, California, USA,Center for Epigenetics and Metabolism, University of California, Irvine, California, USA
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5
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Yu S, Li C, Ji G, Zhang L. The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:783393. [PMID: 34867414 PMCID: PMC8637741 DOI: 10.3389/fphar.2021.783393] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 11/02/2021] [Indexed: 12/26/2022] Open
Abstract
Fructose, especially industrial fructose (sucrose and high fructose corn syrup) is commonly used in all kinds of beverages and processed foods. Liver is the primary organ for fructose metabolism, recent studies suggest that excessive fructose intake is a driving force in non-alcoholic fatty liver disease (NAFLD). Dietary fructose metabolism begins at the intestine, along with its metabolites, may influence gut barrier and microbiota community, and contribute to increased nutrient absorption and lipogenic substrates overflow to the liver. Overwhelming fructose and the gut microbiota-derived fructose metabolites (e.g., acetate, butyric acid, butyrate and propionate) trigger the de novo lipogenesis in the liver, and result in lipid accumulation and hepatic steatosis. Fructose also reprograms the metabolic phenotype of liver cells (hepatocytes, macrophages, NK cells, etc.), and induces the occurrence of inflammation in the liver. Besides, there is endogenous fructose production that expands the fructose pool. Considering the close association of fructose metabolism and NAFLD, the drug development that focuses on blocking the absorption and metabolism of fructose might be promising strategies for NAFLD. Here we provide a systematic discussion of the underlying mechanisms of dietary fructose in contributing to the development and progression of NAFLD, and suggest the possible targets to prevent the pathogenetic process.
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Affiliation(s)
- Siyu Yu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chunlin Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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6
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Wu Y. Molecular phyloecology suggests a trophic shift concurrent with the evolution of the first birds. Commun Biol 2021; 4:547. [PMID: 33986452 PMCID: PMC8119460 DOI: 10.1038/s42003-021-02067-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 03/31/2021] [Indexed: 02/03/2023] Open
Abstract
Birds are characterized by evolutionary specializations of both locomotion (e.g., flapping flight) and digestive system (toothless, crop, and gizzard), while the potential selection pressures responsible for these evolutionary specializations remain unclear. Here we used a recently developed molecular phyloecological method to reconstruct the diets of the ancestral archosaur and of the common ancestor of living birds (CALB). Our results suggest a trophic shift from carnivory to herbivory (fruit, seed, and/or nut eater) at the archosaur-to-bird transition. The evolutionary shift of the CALB to herbivory may have essentially made them become a low-level consumer and, consequently, subject to relatively high predation risk from potential predators such as gliding non-avian maniraptorans, from which birds descended. Under the relatively high predation pressure, ancestral birds with gliding capability may have then evolved not only flapping flight as a possible anti-predator strategy against gliding predatory non-avian maniraptorans but also the specialized digestive system as an evolutionary tradeoff of maximizing foraging efficiency and minimizing predation risk. Our results suggest that the powered flight and specialized digestive system of birds may have evolved as a result of their tropic shift-associated predation pressure.
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Affiliation(s)
- Yonghua Wu
- School of Life Sciences, Northeast Normal University, Changchun, China.
- Jilin Provincial Key Laboratory of Animal Resource Conservation and Utilization, Northeast Normal University, Changchun, China.
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7
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Elferink H, Bruekers JPJ, Veeneman GH, Boltje TJ. A comprehensive overview of substrate specificity of glycoside hydrolases and transporters in the small intestine : "A gut feeling". Cell Mol Life Sci 2020; 77:4799-4826. [PMID: 32506169 PMCID: PMC7658089 DOI: 10.1007/s00018-020-03564-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023]
Abstract
The human body is able to process and transport a complex variety of carbohydrates, unlocking their nutritional value as energy source or as important building block. The endogenous glycosyl hydrolases (glycosidases) and glycosyl transporter proteins located in the enterocytes of the small intestine play a crucial role in this process and digest and/or transport nutritional sugars based on their structural features. It is for these reasons that glycosidases and glycosyl transporters are interesting therapeutic targets to combat sugar related diseases (such as diabetes) or to improve drug delivery. In this review we provide a detailed overview focused on the molecular structure of the substrates involved as a solid base to start from and to fuel research in the area of therapeutics and diagnostics.
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Affiliation(s)
- Hidde Elferink
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, Nijmegen, The Netherlands
| | - Jeroen P J Bruekers
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, Nijmegen, The Netherlands
| | | | - Thomas J Boltje
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, Nijmegen, The Netherlands.
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Gonçalves AS, Andrade N, Martel F. Intestinal fructose absorption: Modulation and relation to human diseases. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch 2020; 472:1207-1248. [PMID: 32829466 PMCID: PMC7462918 DOI: 10.1007/s00424-020-02439-5] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/11/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022]
Abstract
Absorption of monosaccharides is mainly mediated by Na+-D-glucose cotransporter SGLT1 and the facititative transporters GLUT2 and GLUT5. SGLT1 and GLUT2 are relevant for absorption of D-glucose and D-galactose while GLUT5 is relevant for D-fructose absorption. SGLT1 and GLUT5 are constantly localized in the brush border membrane (BBM) of enterocytes, whereas GLUT2 is localized in the basolateral membrane (BLM) or the BBM plus BLM at low and high luminal D-glucose concentrations, respectively. At high luminal D-glucose, the abundance SGLT1 in the BBM is increased. Hence, D-glucose absorption at low luminal glucose is mediated via SGLT1 in the BBM and GLUT2 in the BLM whereas high-capacity D-glucose absorption at high luminal glucose is mediated by SGLT1 plus GLUT2 in the BBM and GLUT2 in the BLM. The review describes functions and regulations of SGLT1, GLUT2, and GLUT5 in the small intestine including diurnal variations and carbohydrate-dependent regulations. Also, the roles of SGLT1 and GLUT2 for secretion of enterohormones are discussed. Furthermore, diseases are described that are caused by malfunctions of small intestinal monosaccharide transporters, such as glucose-galactose malabsorption, Fanconi syndrome, and fructose intolerance. Moreover, it is reported how diabetes, small intestinal inflammation, parental nutrition, bariatric surgery, and metformin treatment affect expression of monosaccharide transporters in the small intestine. Finally, food components that decrease D-glucose absorption and drugs in development that inhibit or downregulate SGLT1 in the small intestine are compiled. Models for regulations and combined functions of glucose transporters, and for interplay between D-fructose transport and metabolism, are discussed.
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Affiliation(s)
- Hermann Koepsell
- Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstr 6, 97070, Würzburg, Germany.
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10
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Al-Jawadi A, Patel CR, Shiarella RJ, Romelus E, Auvinen M, Guardia J, Pearce SC, Kishida K, Yu S, Gao N, Ferraris RP. Cell-Type-Specific, Ketohexokinase-Dependent Induction by Fructose of Lipogenic Gene Expression in Mouse Small Intestine. J Nutr 2020; 150:1722-1730. [PMID: 32386219 PMCID: PMC7330472 DOI: 10.1093/jn/nxaa113] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/06/2020] [Accepted: 04/01/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND High intakes of fructose are associated with metabolic diseases, including hypertriglyceridemia and intestinal tumor growth. Although small intestinal epithelia consist of many different cell types, express lipogenic genes, and convert dietary fructose to fatty acids, there is no information on the identity of the cell type(s) mediating this conversion and on the effects of fructose on lipogenic gene expression. OBJECTIVES We hypothesized that fructose regulates the intestinal expression of genes involved in lipid and apolipoprotein synthesis, that regulation depends on the fructose transporter solute carrier family 2 member a5 [Slc2a5 (glucose transporter 5)] and on ketohexokinase (Khk), and that regulation occurs only in enterocytes. METHODS We compared lipogenic gene expression among different organs from wild-type adult male C57BL mice consuming a standard vivarium nonpurified diet. We then gavaged twice daily for 2.5 d fructose or glucose solutions (15%, 0.3 mL per mouse) into wild-type, Slc2a5-knockout (KO), and Khk-KO mice with free access to the nonpurified diet and determined expression of representative lipogenic genes. Finally, from mice fed the nonpurified diet, we made organoids highly enriched in enterocyte, goblet, Paneth, or stem cells and then incubated them overnight in 10 mM fructose or glucose. RESULTS Most lipogenic genes were significantly expressed in the intestine relative to the kidney, liver, lung, and skeletal muscle. In vivo expression of Srebf1, Acaca, Fasn, Scd1, Dgat1, Gk, Apoa4, and Apob mRNA and of Scd1 protein increased (P < 0.05) by 3- to 20-fold in wild-type, but not in Slc2a5-KO and Khk-KO, mice gavaged with fructose. In vitro, Slc2a5- and Khk-dependent, fructose-induced increases, which ranged from 1.5- to 4-fold (P < 0.05), in mRNA concentrations of all these genes were observed only in organoids enriched in enterocytes. CONCLUSIONS Fructose specifically stimulates expression of mouse small intestinal genes for lipid and apolipoprotein synthesis. Secretory and stem cells seem incapable of transport- and metabolism-dependent lipogenesis, occurring only in absorptive enterocytes.
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Affiliation(s)
- Arwa Al-Jawadi
- Present address for AA-J: Thermo Fisher Scientific, 5823 Newton Drive, Carlsbad, CA 92008 USA
| | - Chirag R Patel
- Present address for CRP: Independent Drug Safety Consultant, 1801 Augustine Cut-off, Wilmington, DE 19803
| | - Reilly J Shiarella
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Emmanuellie Romelus
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Madelyn Auvinen
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Joshua Guardia
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Sarah C Pearce
- Present address for SCP: Performance Nutrition Team, Combat Feeding Directorate, Natick Soldier Research, Development, and Engineering Center (NSRDEC), 15 General Greene Avenue, Natick, MA 01760-5018
| | - Kunihiro Kishida
- Present address for KK: Department of Science and Technology on Food Safety, Kindai University, Wakayama 649-6493, Japan
| | - Shiyan Yu
- Department of Biological Sciences, Life Science Center, Rutgers University, Newark, NJ, USA
| | - Nan Gao
- Department of Biological Sciences, Life Science Center, Rutgers University, Newark, NJ, USA
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Merino B, Fernández-Díaz CM, Cózar-Castellano I, Perdomo G. Intestinal Fructose and Glucose Metabolism in Health and Disease. Nutrients 2019; 12:E94. [PMID: 31905727 PMCID: PMC7019254 DOI: 10.3390/nu12010094] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/26/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023] Open
Abstract
The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.
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Affiliation(s)
- Beatriz Merino
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Cristina M. Fernández-Díaz
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain
| | - German Perdomo
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos 09001, Spain
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12
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Sato T, Watanabe Y, Nishimura Y, Inoue M, Morita A, Miura S. Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway. Biochem Biophys Rep 2019; 18:100638. [PMID: 31032430 PMCID: PMC6479072 DOI: 10.1016/j.bbrep.2019.100638] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/19/2019] [Accepted: 04/08/2019] [Indexed: 11/21/2022] Open
Abstract
Excessive intake of fructose increases lipogenesis in the liver, leading to hepatic lipid accumulation and development of fatty liver disease. Metabolic alterations in the liver due to fructose intake have been reported in many studies, but the effect of fructose administration on hepatic gluconeogenesis is not fully understood. The aim of this study was to evaluate the acute effects of fructose administration on fasting-induced hepatic gluconeogenesis. C57BL/6J mice were administered fructose solution after 14 h of fasting and plasma insulin, glucose, free fatty acids, and ketone bodies were analysed. We also measured phosphorylated AKT and forkhead box O (FoxO) 1 protein levels and gene expression related to gluconeogenesis in the liver. Furthermore, we measured glucose production from pyruvate after fructose administration. Glucose-administered mice were used as controls. Fructose administration enhanced phosphorylation of AKT in the liver, without increase of blood insulin levels. Blood free fatty acids and ketone bodies concentrations were as high as those in the fasting group after fructose administration, suggesting that insulin-induced inhibition of lipolysis did not occur in mice administered with fructose. Fructose also enhanced phosphorylation of FoxO1 and suppressed gluconeogenic gene expression, glucose-6-phosphatase activity, and glucose production from pyruvate. The present study suggests that acute fructose administration suppresses fasting-induced hepatic gluconeogenesis in an insulin-independent manner.
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Key Words
- AKT
- CREB, cAMP response element binding protein
- ChREBP, carbohydrate response element binding protein
- EDTA, ethylenediaminetetraacetic acid
- FFA, free fatty acid
- FoxO, forkhead box O
- FoxO1
- Fructose
- G6Pase
- G6Pase, glucose-6-phosphatase
- Gluconeogenesis
- Insulin
- PEPCK, phosphoenolpyruvate carboxykinase
- PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha
- PI3K, phosphoinositide-3-kinase
- PIP 3, phosphatidylinositol-(3,4,5)-trisphosphate
- SREBP, sterol-regulatory element binding protein
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Affiliation(s)
- Tomoki Sato
- Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
- Research Fellow of Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan
| | - Yui Watanabe
- Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Yuri Nishimura
- Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Mizuki Inoue
- Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Akihito Morita
- Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Shinji Miura
- Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
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13
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Abstract
Increased understanding of fructose metabolism, which begins with uptake via the intestine, is important because fructose now constitutes a physiologically significant portion of human diets and is associated with increased incidence of certain cancers and metabolic diseases. New insights in our knowledge of intestinal fructose absorption mediated by the facilitative glucose transporter GLUT5 in the apical membrane and by GLUT2 in the basolateral membrane are reviewed. We begin with studies related to structure as well as ligand binding, then revisit the controversial proposition that apical GLUT2 is the main mediator of intestinal fructose absorption. The review then describes how dietary fructose may be sensed by intestinal cells to affect the expression and activity of transporters and fructolytic enzymes, to interact with the transport of certain minerals and electrolytes, and to regulate portal and peripheral fructosemia and glycemia. Finally, it discusses the potential contributions of dietary fructose to gastrointestinal diseases and to the gut microbiome.
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Affiliation(s)
- Ronaldo P Ferraris
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey 07946, USA;
| | - Jun-Yong Choe
- Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, Illinois 60064, USA;
| | - Chirag R Patel
- Independent Drug Safety Consulting, Wilmington, Delaware 19803, USA;
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14
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Kishida K, Pearce SC, Yu S, Gao N, Ferraris RP. Nutrient sensing by absorptive and secretory progenies of small intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 2017; 312:G592-G605. [PMID: 28336548 PMCID: PMC5495913 DOI: 10.1152/ajpgi.00416.2016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 01/31/2023]
Abstract
Nutrient sensing triggers responses by the gut-brain axis modulating hormone release, feeding behavior and metabolism that become dysregulated in metabolic syndrome and some cancers. Except for absorptive enterocytes and secretory enteroendocrine cells, the ability of many intestinal cell types to sense nutrients is still unknown; hence we hypothesized that progenitor stem cells (intestinal stem cells, ISC) possess nutrient sensing ability inherited by progenies during differentiation. We directed via modulators of Wnt and Notch signaling differentiation of precursor mouse intestinal crypts into specialized organoids each containing ISC, enterocyte, goblet, or Paneth cells at relative proportions much higher than in situ as determined by mRNA expression and immunocytochemistry of cell type biomarkers. We identified nutrient sensing cell type(s) by increased expression of fructolytic genes in response to a fructose challenge. Organoids comprised primarily of enterocytes, Paneth, or goblet, but not ISC, cells responded specifically to fructose without affecting nonfructolytic genes. Sensing was independent of Wnt and Notch modulators and of glucose concentrations in the medium but required fructose absorption and metabolism. More mature enterocyte- and goblet-enriched organoids exhibited stronger fructose responses. Remarkably, enterocyte organoids, upon forced dedifferentiation to reacquire ISC characteristics, exhibited a markedly extended lifespan and retained fructose sensing ability, mimicking responses of some dedifferentiated cancer cells. Using an innovative approach, we discovered that nutrient sensing is likely repressed in progenitor ISCs then irreversibly derepressed during specification into sensing-competent absorptive or secretory lineages, the surprising capacity of Paneth and goblet cells to detect fructose, and the important role of differentiation in modulating nutrient sensing.NEW & NOTEWORTHY Small intestinal stem cells differentiate into several cell types transiently populating the villi. We used specialized organoid cultures each comprised of a single cell type to demonstrate that 1) differentiation seems required for nutrient sensing, 2) secretory goblet and Paneth cells along with enterocytes sense fructose, suggesting that sensing is acquired after differentiation is triggered but before divergence between absorptive and secretory lineages, and 3) forcibly dedifferentiated enterocytes exhibit fructose sensing and lifespan extension.
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Affiliation(s)
- Kunihiro Kishida
- 1Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
| | - Sarah C. Pearce
- 1Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
| | - Shiyan Yu
- 2Department of Biological Sciences, Life Science Center, Rutgers University, Newark, New Jersey
| | - Nan Gao
- 2Department of Biological Sciences, Life Science Center, Rutgers University, Newark, New Jersey
| | - Ronaldo P. Ferraris
- 1Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
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15
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Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling. Inflammation 2016; 39:16-29. [PMID: 26242865 DOI: 10.1007/s10753-015-0218-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3β signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3β signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p-Akt, p-GSK3β, and its own expression. TGF-β treatment could increase expression of PI3K, p-Akt, p-GSK3β, and WISP1. SH-5 treatment could partly suppress TGF-β-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3β and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3β-dependent noncanonical TGF-β signaling.
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16
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Herman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends Endocrinol Metab 2016; 27:719-730. [PMID: 27387598 PMCID: PMC5035631 DOI: 10.1016/j.tem.2016.06.005] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/06/2016] [Accepted: 06/09/2016] [Indexed: 01/04/2023]
Abstract
Epidemiological studies link fructose consumption with metabolic disease, an association attributable in part to fructose-mediated lipogenesis. The mechanisms governing fructose-induced lipogenesis and disease remain debated. Acutely, fructose increases de novo lipogenesis through the efficient and uninhibited action of ketohexokinase and aldolase B which yields substrates for fatty-acid synthesis. Chronic fructose consumption further enhances the capacity for hepatic fructose metabolism by activating several key transcription factors (i.e., SREBP1c and ChREBP) which augment the expression of lipogenic enzymes, increasing lipogenesis and further compounding hypertriglyceridemia and hepatic steatosis. Hepatic insulin resistance develops from diacylglycerol-PKCɛ-mediated impairment of insulin signaling and possibly additional mechanisms. Initiatives that decrease fructose consumption and therapies that block fructose-mediated lipogenesis will be necessary to avert future metabolic pandemics.
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Affiliation(s)
- Mark A Herman
- Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
| | - Varman T Samuel
- Yale University School of Medicine, 950 Campbell Avenue, West Haven, CT 06516, USA; Veterans Affairs Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA.
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17
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Barron CC, Bilan PJ, Tsakiridis T, Tsiani E. Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism 2016; 65:124-39. [PMID: 26773935 DOI: 10.1016/j.metabol.2015.10.007] [Citation(s) in RCA: 294] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 09/22/2015] [Accepted: 10/01/2015] [Indexed: 12/11/2022]
Abstract
It is long recognized that cancer cells display increased glucose uptake and metabolism. In a rate-limiting step for glucose metabolism, the glucose transporter (GLUT) proteins facilitate glucose uptake across the plasma membrane. Fourteen members of the GLUT protein family have been identified in humans. This review describes the major characteristics of each member of the GLUT family and highlights evidence of abnormal expression in tumors and cancer cells. The regulation of GLUTs by key proliferation and pro-survival pathways including the phosphatidylinositol 3-kinase (PI3K)-Akt, hypoxia-inducible factor-1 (HIF-1), Ras, c-Myc and p53 pathways is discussed. The clinical utility of GLUT expression in cancer has been recognized and evidence regarding the use of GLUTs as prognostic or predictive biomarkers is presented. GLUTs represent attractive targets for cancer therapy and this review summarizes recent studies in which GLUT1, GLUT3, GLUT5 and others are inhibited to decrease cancer growth.
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Affiliation(s)
- Carly C Barron
- Department of Health Sciences, Brock University, St. Catharines, ON, L2S 3A1, Canada
| | - Philip J Bilan
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Theodoros Tsakiridis
- Department of Oncology, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON, L2S 3A1, Canada.
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18
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Patel C, Douard V, Yu S, Gao N, Ferraris RP. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. FASEB J 2015; 29:4046-58. [PMID: 26071406 PMCID: PMC4550372 DOI: 10.1096/fj.15-272195] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 06/02/2015] [Indexed: 01/03/2023]
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.
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Affiliation(s)
- Chirag Patel
- *Department of Pharmacology and Physiology, New Jersey Medical School, and Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Veronique Douard
- *Department of Pharmacology and Physiology, New Jersey Medical School, and Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Shiyan Yu
- *Department of Pharmacology and Physiology, New Jersey Medical School, and Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Nan Gao
- *Department of Pharmacology and Physiology, New Jersey Medical School, and Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
| | - Ronaldo P Ferraris
- *Department of Pharmacology and Physiology, New Jersey Medical School, and Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA
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19
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Patel C, Douard V, Yu S, Tharabenjasin P, Gao N, Ferraris RP. Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK. Am J Physiol Regul Integr Comp Physiol 2015; 309:R499-509. [PMID: 26084694 DOI: 10.1152/ajpregu.00128.2015] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 06/16/2015] [Indexed: 01/09/2023]
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.
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Affiliation(s)
- Chirag Patel
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
| | - Veronique Douard
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
| | - Shiyan Yu
- Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey
| | - Phuntila Tharabenjasin
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
| | - Nan Gao
- Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey
| | - Ronaldo P Ferraris
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and
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20
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Coon SD, Rajendran VM, Schwartz JH, Singh SK. Glucose-dependent insulinotropic polypeptide-mediated signaling pathways enhance apical PepT1 expression in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2015; 308:G56-62. [PMID: 25377315 PMCID: PMC4281688 DOI: 10.1152/ajpgi.00168.2014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We have shown recently that glucose-dependent insulinotropic polypeptide (GIP), but not glucagon-like peptide 1 (GLP-1) augments H(+) peptide cotransporter (PepT1)-mediated peptide absorption in murine jejunum. While we observed that inhibiting cAMP production decreased this augmentation of PepT1 activity by GIP, it was unclear whether PKA and/or other regulators of cAMP signaling pathway(s) were involved. This study utilized tritiated glycyl-sarcosine [(3)H-glycyl-sarcosine (Gly-Sar), a relatively nonhydrolyzable dipeptide] uptake to measure PepT1 activity in CDX2-transfected IEC-6 (IEC-6/CDX2) cells, an absorptive intestinal epithelial cell model. Similar to our earlier observations with mouse jejunum, GIP but not GLP-1 augmented Gly-Sar uptake (control vs. +GIP: 154 ± 22 vs. 454 ± 39 pmol/mg protein; P < 0.001) in IEC-6/CDX2 cells. Rp-cAMP (a PKA inhibitor) and wortmannin [phosophoinositide-3-kinase (PI3K) inhibitor] pretreatment completely blocked, whereas neither calphostin C (a potent PKC inhibitor) nor BAPTA (an intracellular Ca(2+) chelator) pretreatment affected the GIP-augmented Gly-Sar uptake in IEC-6/CDX2 cells. The downstream metabolites Epac (control vs. Epac agonist: 287 ± 22 vs. 711 ± 80 pmol/mg protein) and AKT (control vs. AKT inhibitor: 720 ± 50 vs. 75 ± 19 pmol/mg protein) were shown to be involved in GIP-augmented PepT1 activity as well. Western blot analyses revealed that both GIP and Epac agonist pretreatment enhance the PepT1 expression on the apical membranes, which is completely blocked by wortmannin in IEC-6/CDX2 cells. These observations demonstrate that both cAMP and PI3K signaling pathways augment GIP-induced peptide uptake through Epac and AKT-mediated pathways in intestinal epithelial cells, respectively. In addition, these observations also indicate that both Epac and AKT-mediated signaling pathways increase apical membrane expression of PepT1 in intestinal absorptive epithelial cells.
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Affiliation(s)
- Steven D. Coon
- 1Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; ,2Department of Medicine, Boston Veterans Affairs Healthcare System, Boston, Massachusetts; ,3Department of Medicine, Boston University Clinical & Translational Science Institute, Boston, Massachusetts; and
| | - Vazhaikkurichi M. Rajendran
- 4Department of Biochemistry and Molecular Biology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - John H. Schwartz
- 1Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
| | - Satish K. Singh
- 1Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; ,2Department of Medicine, Boston Veterans Affairs Healthcare System, Boston, Massachusetts;
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21
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Rodríguez-Yoldi MJ, Gascón S, Barranquero C, García-Barrios A, Osada J. Involvement of intracellular signaling in the IL-1β inhibitory effect on fructose intestinal absorption. J Cell Physiol 2014; 230:896-902. [PMID: 25216359 DOI: 10.1002/jcp.24820] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 09/05/2014] [Indexed: 01/02/2023]
Abstract
A variety of bacteria and their excreted/secreted products having direct effects on epithelial ion transport and permeability and the release of cytokines during bacterial infection may impact directly on epithelial function. Interleukin-1β (IL-1β) is a pleiotropic cytokine that affects the intestinal absorption of nutrients. The aim of this work was to study the intracellular signaling pathways involved in the inhibitory effect of IL-1β on D-fructose intestinal transport in rabbit jejunum and Caco-2 cells. The results show that the cytokine inhibitory effect was completely reversed in presence of proteasome or PKC selective inhibitors in IL-1β treated rabbits. In addition, the activation of PI3K abolished the IL-1β effect. Likewise, these results were confirmed in Caco-2 cells. In addition, p-PI3K expression was increased by IL-1β-treatment whereas the expression of p-PKCα was not significantly affected. In summary, the results suggest that IL-1β could regulate the activation of pPKCα 73, pPI3K 55, and NF-kB proteins. These events could exert an inhibitory effect on fructose intestinal absorption by a modification of GLUT5 insertion to brush-border membrane and/or the functional transporter activity. This effect is independent of hormonal milieu and nervous stimuli.
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Affiliation(s)
- María J Rodríguez-Yoldi
- Physiology Unit, Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Spain
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22
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Wilder-Smith CH, Li X, Ho SS, Leong SM, Wong RK, Koay ES, Ferraris RP. Fructose transporters GLUT5 and GLUT2 expression in adult patients with fructose intolerance. United European Gastroenterol J 2014; 2:14-21. [PMID: 24918004 DOI: 10.1177/2050640613505279] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 08/24/2013] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Gastrointestinal symptoms and malabsorption following fructose ingestion (fructose intolerance) are common in functional gastrointestinal disorders (FGID). The underlying mechanism is unclear, but is hypothesized to be related an abnormality of intestinal fructose transporter proteins. OBJECTIVE To assess the expression of the main intestinal fructose transporter proteins, glucose transport protein 5 (GLUT5) and 2 (GLUT2), in FGID. METHODS The expression of GLUT5 and GLUT2 protein and mRNA in small intestinal biopsy tissue was investigated using real-time reverse-transcription PCR and Western immunoblotting in 11 adults with FGID and fructose intolerance ascertained by breath testing and in 15 controls. RESULTS Median expression levels of GLUT5 mRNA normalized to beta-actin were 0.18 (interquartile range, IQR, 0.13-0.21) in patients and 0.17 (IQR 0.12-0.19) in controls (p > 0.05). Respective levels of GLUT2 mRNA were 0.26 (IQR 0.20-0.31) and 0.26 (IQR 0.19-0.31) (p > 0.05). Median expression levels of GLUT5 protein normalized to alpha-tubulin were 0.95 (IQR 0.52-1.68) in patients and 0.95 (IQR 0.59-1.15) in controls (p > 0.05). Respective protein expression levels for GLUT2 were 1.56 (IQR 1.06-2.14) and 1.35 (IQR 0.96-1.79) (p > 0.05). CONCLUSIONS Human fructose intolerance may not be associated with marked changes in GLUT5 and GLUT2 expression. Replication of these results in a larger subject group, including measures of transporter activation and membrane and subcellular localization, is warranted.
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Affiliation(s)
- Clive H Wilder-Smith
- Brain-Gut Research Group, Bern, Switzerland ; Neurogastroenterology Unit, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Xinhua Li
- Neurogastroenterology Unit, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Sherry Sy Ho
- Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore
| | - Sai Mun Leong
- Neurogastroenterology Unit, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Reuben K Wong
- Neurogastroenterology Unit, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Evelyn Sc Koay
- Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore ; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
| | - Ronaldo P Ferraris
- Department of Pharmacology & Physiology, UMDNJ - New Jersey Medical School, Newark, USA
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23
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Thazhath SS, Wu T, Young RL, Horowitz M, Rayner CK. Glucose absorption in small intestinal diseases. Expert Rev Gastroenterol Hepatol 2014; 8:301-312. [PMID: 24502537 DOI: 10.1586/17474124.2014.887439] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Recent developments in the field of diabetes and obesity management have established the central role of the gut in glucose homeostasis; not only is the gut the primary absorptive site, but it also triggers neurohumoral feedback responses that regulate the pre- and post-absorptive phases of glucose metabolism. Structural and/or functional disorders of the intestine have the capacity to enhance (e.g.: diabetes) or inhibit (e.g.: short-gut syndrome, critical illness) glucose absorption, with potentially detrimental outcomes. In this review, we first describe the normal physiology of glucose absorption and outline the methods by which it can be quantified. Then we focus on the structural and functional changes in the small intestine associated with obesity, critical illness, short gut syndrome and other malabsorptive states, and particularly Type 2 diabetes, which can impact upon carbohydrate absorption and overall glucose homeostasis.
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Affiliation(s)
- Sony S Thazhath
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Adelaide, SA, Australia
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24
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Viñuales C, Gascón S, Barranquero C, Osada J, Rodríguez-Yoldi MJ. Interleukin-1beta reduces galactose transport in intestinal epithelial cells in a NF-kB and protein kinase C-dependent manner. Vet Immunol Immunopathol 2013; 155:171-81. [DOI: 10.1016/j.vetimm.2013.06.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 06/05/2013] [Accepted: 06/18/2013] [Indexed: 02/08/2023]
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25
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A role for WNT1-inducible signaling protein-1 in airway remodeling in a rat asthma model. Int Immunopharmacol 2013; 17:350-7. [PMID: 23845395 DOI: 10.1016/j.intimp.2013.06.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 06/10/2013] [Accepted: 06/10/2013] [Indexed: 12/22/2022]
Abstract
Over-expression of WISP1 has been described in multi-organ fibrosis and tissue remodeling. Moreover, it has recently been found that polymorphism of WISP1 gene is related with the change of lung function in asthmatic subjects. Therefore, we hypothesized that WISP1 might be closely linked to occurrence and development of asthmatic airway remodeling. Aim of this study was to examine the roles of WISP1 in an asthmatic model with airway remodeling and assess the specific effects of WISP1 on human lung fibroblast in vitro. Animal models were developed by challenged with ovalbumin. The levels of WISP1 expression in animal models were assessed by real-time PCR and immunohistochemistry. To examine the specific effects of WISP1 on airway remodeling, WISP1 was depleted by neutralizing α-WISP1 antibodies in vivo. Moreover, human lung fibroblast (HFL-1) was challenged with WISP1 in the presence and absence of SH-5 in vitro. Our study showed that OVA exposure increased the levels of WISP1 expression in a rat asthma model. WISP1 depletion could partially inhibit OVA-induced airway remodeling. In vitro, WISP1-treated HFL-1 cells presented abnormal proliferation and over-expression of Col1a1 and Fn1. However, WISP1-induced collagen release from HFL-1 cells could be attenuated by pretreatment with an Akt inhibitor. Moreover, the levels of p-Akt and p-GSK-3β in WISP1-treated HFL-1 cells were also significantly elevated. In summary, WISP1 might initiate and perpetuate the pathological remodeling of asthma by inducing fibroblast proliferation and ECM deposition. The specific effects of WISP1 were likely due to activation of pulmonary Akt/GSK-3β signaling.
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26
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Shirazi-Beechey SP, Moran AW, Bravo D, Al-Rammahi M. NONRUMINANT NUTRITION SYMPOSIUM: Intestinal glucose sensing and regulation of glucose absorption: Implications for swine nutrition1. J Anim Sci 2011; 89:1854-62. [DOI: 10.2527/jas.2010-3695] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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27
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Diet-induced epigenetic regulation in vivo of the intestinal fructose transporter Glut5 during development of rat small intestine. Biochem J 2011; 435:43-53. [PMID: 21222652 DOI: 10.1042/bj20101987] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Metabolic complications arising from excessive fructose consumption are increasing dramatically even in young children, but little is known about ontogenetic mechanisms regulating Glut5 [glucose transporter 5; encoded by the Slc2a5 (solute carrier family 2 member 5) gene]. Glut5 expression is low postnatally and does not increase, unless luminal fructose and systemic glucocorticoids are present, until ≥ 14 days of age, suggesting substrate-inducible age- and hormone-sensitive regulation. In the present study, we perfused intestines of 10- and 20-day-old rats with either fructose or glucose then analysed the binding of Pol II (RNA polymerase II) and GR (glucocorticoid receptor), as well as acetylation of histones H3 and H4 by chromatin immunoprecipitation. Abundance of Glut5 mRNA increased only with fructose perfusion and age, a pattern that matched that of Pol II binding and histone H3 acetylation to the Glut5 promoter. Although many regions of the Glut5 promoter respond to developmental signals, fewer regions perceive dietary signals. Age- but not fructose-dependent expression of Sglt1 [sodium-dependent glucose co-transporter 1 encoded by the Slc5a1(solute carrier family 5 member 1) gene] also correlated with Pol II binding and histone H3 acetylation. In contrast, G6Pase (glucose-6-phosphatase; encoded by the G6pc gene) expression, which decreases with age and increases with fructose, is associated only with age-dependent changes in histone H4 acetylation. Induction of Glut5 during ontogenetic development appears to be specifically mediated by GR translocation to the nucleus and subsequent binding to the Glut5 promoter, whereas the glucocorticoid-independent regulation of Sglt1 by age was not associated with any GR binding to the Sglt1 promoter.
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Abstract
While virtually absent in our diet a few hundred years ago, fructose has now become a major constituent of our modern diet. Our main sources of fructose are sucrose from beet or cane, high fructose corn syrup, fruits, and honey. Fructose has the same chemical formula as glucose (C(6)H(12)O(6)), but its metabolism differs markedly from that of glucose due to its almost complete hepatic extraction and rapid hepatic conversion into glucose, glycogen, lactate, and fat. Fructose was initially thought to be advisable for patients with diabetes due to its low glycemic index. However, chronically high consumption of fructose in rodents leads to hepatic and extrahepatic insulin resistance, obesity, type 2 diabetes mellitus, and high blood pressure. The evidence is less compelling in humans, but high fructose intake has indeed been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Hepatic de novo lipogenesis and lipotoxicity, oxidative stress, and hyperuricemia have all been proposed as mechanisms responsible for these adverse metabolic effects of fructose. Although there is compelling evidence that very high fructose intake can have deleterious metabolic effects in humans as in rodents, the role of fructose in the development of the current epidemic of metabolic disorders remains controversial. Epidemiological studies show growing evidence that consumption of sweetened beverages (containing either sucrose or a mixture of glucose and fructose) is associated with a high energy intake, increased body weight, and the occurrence of metabolic and cardiovascular disorders. There is, however, no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects. There has also been much concern that consumption of free fructose, as provided in high fructose corn syrup, may cause more adverse effects than consumption of fructose consumed with sucrose. There is, however, no direct evidence for more serious metabolic consequences of high fructose corn syrup versus sucrose consumption.
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Affiliation(s)
- Luc Tappy
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland.
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Sakar Y, Nazaret C, Lettéron P, Ait Omar A, Avenati M, Viollet B, Ducroc R, Bado A. Positive regulatory control loop between gut leptin and intestinal GLUT2/GLUT5 transporters links to hepatic metabolic functions in rodents. PLoS One 2009; 4:e7935. [PMID: 19956534 PMCID: PMC2780353 DOI: 10.1371/journal.pone.0007935] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2009] [Accepted: 10/08/2009] [Indexed: 12/18/2022] Open
Abstract
Background and Aims The small intestine is the major site of absorption of dietary sugars. The rate at which they enter and exit the intestine has a major effect on blood glucose homeostasis. In this study, we determine the effects of luminal leptin on activity/expression of GLUT2 and GLUT5 transporters in response to sugars intake and analyse their physiological consequences. Methodology Wistar rats, wild type and AMPKα2−/− mice were used. In vitro and in vivo isolated jejunal loops were used to quantify transport of fructose and galactose in the absence and the presence of leptin. The effects of fructose and galactose on gastric leptin release were determined. The effects of leptin given orally without or with fructose were determined on the expression of GLUT2/5, on some gluconeogenesis and lipogenic enzymes in the intestine and the liver. Principal Findings First, in vitro luminal leptin activating its receptors coupled to PKCβII and AMPKα, increased insertion of GLUT2/5 into the brush-border membrane leading to enhanced galactose and fructose transport. Second in vivo, oral fructose but not galactose induced in mice a rapid and potent release of gastric leptin in gastric juice without significant changes in plasma leptin levels. Moreover, leptin given orally at a dose reproducing comparable levels to those induced by fructose, stimulated GLUT5-fructose transport, and potentiated fructose-induced: i) increase in blood glucose and mRNA levels of key gluconeogenesis enzymes; ii) increase in blood triglycerides and reduction of mRNA levels of intestinal and hepatic Fasting-induced adipocyte factor (Fiaf) and iii) increase in SREBP-1c, ACC-1, FAS mRNA levels and dephosphorylation/activation of ACC-1 in liver. Conclusion/Significance These data identify for the first time a positive regulatory control loop between gut leptin and fructose in which fructose triggers release of gastric leptin which, in turn, up-regulates GLUT5 and concurrently modulates metabolic functions in the liver. This loop appears to be a new mechanism (possibly pathogenic) by which fructose consumption rapidly becomes highly lipogenic and deleterious.
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Affiliation(s)
- Yassine Sakar
- INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon, UFR de Médecine Paris 7 - Denis Diderot, IFR02 Claude Bernard, Paris, France
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Roche M, Neti PVSV, Kemp FW, Agrawal A, Attanasio A, Douard V, Muduli A, Azzam EI, Norkus E, Brimacombe M, Howell RW, Ferraris RP. Radiation-induced reductions in transporter mRNA levels parallel reductions in intestinal sugar transport. Am J Physiol Regul Integr Comp Physiol 2009; 298:R173-82. [PMID: 19907007 DOI: 10.1152/ajpregu.00612.2009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
More than a century ago, ionizing radiation was observed to damage the radiosensitive small intestine. Although a large number of studies has since shown that radiation reduces rates of intestinal digestion and absorption of nutrients, no study has determined whether radiation affects mRNA expression and dietary regulation of nutrient transporters. Since radiation generates free radicals and disrupts DNA replication, we tested the hypotheses that at doses known to reduce sugar absorption, radiation decreases the mRNA abundance of sugar transporters SGLT1 and GLUT5, prevents substrate regulation of sugar transporter expression, and causes reductions in sugar absorption that can be prevented by consumption of the antioxidant vitamin A, previously shown by us to radioprotect the testes. Mice were acutely irradiated with (137)Cs gamma rays at doses of 0, 7, 8.5, or 10 Gy over the whole body. Mice were fed with vitamin A-supplemented diet (100x the control diet) for 5 days prior to irradiation after which the diet was continued until death. Intestinal sugar transport was studied at days 2, 5, 8, and 14 postirradiation. By day 8, d-glucose uptake decreased by approximately 10-20% and d-fructose uptake by 25-85%. With increasing radiation dose, the quantity of heterogeneous nuclear RNA increased for both transporters, whereas mRNA levels decreased, paralleling reductions in transport. Enterocytes of mice fed the vitamin A supplement had > or = 6-fold retinol concentrations than those of mice fed control diets, confirming considerable intestinal vitamin A uptake. However, vitamin A supplementation had no effect on clinical or transport parameters and afforded no protection against radiation-induced changes in intestinal sugar transport. Radiation markedly reduced GLUT5 activity and mRNA abundance, but high-d-fructose diets enhanced GLUT5 activity and mRNA expression in both unirradiated and irradiated mice. In conclusion, the effect of radiation may be posttranscriptional, and radiation-damaged intestines can still respond to dietary stimuli.
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Affiliation(s)
- Marjolaine Roche
- Department of Pharmacology and Physiology, New Jersey Medical School, NJ, USA
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Mochizuki K, Yorita S, Goda T. Gene expression changes in the jejunum of rats during the transient suckling-weaning period. J Nutr Sci Vitaminol (Tokyo) 2009; 55:139-48. [PMID: 19436140 DOI: 10.3177/jnsv.55.139] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
It is well-known that the small intestine of rodents rapidly undergoes differentiation and maturation during the transient suckling-weaning period from postnatal days 13 to 27. In the present study, we examined the gene expression changes in the jejunum of rats during the transient suckling-weaning period by microarray analysis. In the microarray data, we found that the expressions of many genes related to digestion/absorption/excretion of nutrients/ions, such as members of the solute carrier (Slc) family and ATP-binding cassette (Abc) subfamily, were rapidly induced during this period. Furthermore, some transcriptional factors/cofactors (Thrsp, Ppargc1a, Klf15 and Vdr), which are presumably important for the induction of intestinal gene expression after weaning, were rapidly induced during this period. In contrast, genes related to transport of nutrients, such as folate, zinc, fat and phosphate, which are important for early development, were highly expressed in the suckling period and then gradually decreased during weaning. These results indicate that the jejunum matures during the suckling-weaning period accompanied by changes in the expression of many genes related to digestion/absorption/excretion and some genes for transcriptional factors/cofactors.
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Affiliation(s)
- Kazuki Mochizuki
- Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences and Global COE, The University of Shizuoka, Shizuoka, Japan
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Dyer J, Al-Rammahi M, Waterfall L, Salmon KSH, Geor RJ, Bouré L, Edwards GB, Proudman CJ, Shirazi-Beechey SP. Adaptive response of equine intestinal Na+/glucose co-transporter (SGLT1) to an increase in dietary soluble carbohydrate. Pflugers Arch 2008; 458:419-30. [PMID: 19048283 DOI: 10.1007/s00424-008-0620-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Accepted: 11/06/2008] [Indexed: 11/26/2022]
Abstract
Experimental and epidemiological evidence suggests that consumption of hydrolyzable carbohydrate, hCHO (grain), by horses is an important risk factor for colic, a common cause of equine mortality. It is unknown whether the small intestinal capacity to digest hCHO and/or to absorb monosaccharides is limiting, or even if horses can adapt to increased carbohydrate load. We investigated changes in the brush-border membrane carbohydrate digestive enzymes and glucose absorptive capacity of horse small intestine in response to increased hCHO. Expression of the Na(+)/glucose co-transporter, SGLT1, was assessed by Western blotting, immunohistochemistry, Northern blotting, QPCR, and Na(+)-dependent D-glucose transport. Glucose transport rates, SGLT1 protein, and mRNA expression were all 2-fold higher in the jejunum and 3- to 5-fold higher in the ileum of horses maintained on a hCHO-enriched diet compared to pasture forage. Activity of the disaccharidases was unaltered by diet. In a well-controlled study, we determined SGLT1 expression in the duodenal and ileal biopsies of horses switched, gradually over a 2-month period, from low (<1.0 g/kg bwt/day) to high hCHO (6.0 g/kg bwt/day) diets of known composition. We show that SGLT1 expression is enhanced, with time, 2-fold in the duodenum and 3.3-fold in the ileum. The study has important implications for dietary management of the horse.
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Affiliation(s)
- Jane Dyer
- Epithelial Function and Development Group, Department of Veterinary Preclinical Sciences, The University of Liverpool, Brownlow Hill and Crown Street, Liverpool L69 7ZJ, UK
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Abstract
We have previously reported that dietary fructose rapidly induces jejunal sucrase–isomaltase (SI) gene expression in rats. In this study, we confirmed in mice that SI mRNA was induced 6 h after force-feeding fructose, but not glucose. Using the chromatin immunoprecipitation assay, we revealed that histones H3 and H4 on the promoter/enhancer regions of the SI gene in mice given fructose were highly acetylated, compared with those given glucose or water. These results suggest that acute induction of SI gene expression by dietary fructose is associated with acetylation of histones H3 and H4 on the SI gene.
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Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab 2008; 295:E227-37. [PMID: 18398011 PMCID: PMC2652499 DOI: 10.1152/ajpendo.90245.2008] [Citation(s) in RCA: 324] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2008] [Accepted: 03/27/2008] [Indexed: 12/11/2022]
Abstract
Fructose is now such an important component of human diets that increasing attention is being focused on the fructose transporter GLUT5. In this review, we describe the regulation of GLUT5 not only in the intestine and testis, where it was first discovered, but also in the kidney, skeletal muscle, fat tissue, and brain where increasing numbers of cell types have been found to have GLUT5. GLUT5 expression levels and fructose uptake rates are also significantly affected by diabetes, hypertension, obesity, and inflammation and seem to be induced during carcinogenesis, particularly in the mammary glands. We end by highlighting research areas that should yield information needed to better understand the role of GLUT5 during normal development, metabolic disturbances, and cancer.
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Affiliation(s)
- Veronique Douard
- Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07101, USA
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Douard V, Choi HI, Elshenawy S, Lagunoff D, Ferraris RP. Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus. J Physiol 2008; 586:3657-73. [PMID: 18556366 DOI: 10.1113/jphysiol.2008.155226] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Fructose consumption has increased dramatically but little is known about mechanisms regulating the intestinal fructose transporter GLUT5 in vivo. In neonatal rats, GLUT5 can be induced only by luminal fructose and only after 14 days of age, unless the gut is primed with dexamethasone prior to fructose perfusion. To elucidate the mechanisms underlying dexamethasone modulation of GLUT5 development, we first identified the receptor mediating its effects then determined whether those effects were genomic. The glucocorticoid receptor (GR) antagonist RU486 dose-dependently prevented the dexamethasone-mediated effects on body weight, intestinal arginase2 (a known GR-regulated gene) and GLUT5. In contrast, an antagonist of the mineralocorticoid receptor as well as agonists of progesterone (PR) and pregnane-X (PXR) receptors did not block the effects of dexamethasone. These receptor antagonists and agonists had no effect on the intestinal glucose transporter SGLT1. Translocation of the GR into the enterocyte nucleus occurred only in dexamethasone-injected pups perfused with fructose, was accompanied by marked increases in brush border GLUT5 abundance, and was blocked by RU486. A priming duration of approximately 24 h is optimal for induction but actinomycin D injection before dexamethasone priming prevented dexamethasone from allowing luminal fructose to induce GLUT5. Actinomycin D had no effect on dexamethasone-independent fructose-induced increases in glucose-6-phosphatase mRNA abundance, suggesting that it did not prevent fructose-induction of GLUT5, but instead prevented dexamethasone-induced synthesis of an intermediate required by fructose for GLUT5 regulation. In suckling rats < 14 days old, developmental regulation of transporters may involve cross-talk between hormonal signals modulating intestinal maturation and nutrient signals regulating specific transporters.
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Affiliation(s)
- Véronique Douard
- Department of Pharmacology and Physiology, NJ Medical School, 185 S. Orange Avenue, Newark, NJ 07101, USA
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Kirchner S, Muduli A, Casirola D, Prum K, Douard V, Ferraris RP. Luminal fructose inhibits rat intestinal sodium-phosphate cotransporter gene expression and phosphate uptake. Am J Clin Nutr 2008; 87:1028-38. [PMID: 18400728 PMCID: PMC2430509 DOI: 10.1093/ajcn/87.4.1028] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND While searching by microarray for sugar-responsive genes, we inadvertently discovered that sodium-phosphate cotransporter 2B (NaPi-2b) mRNA concentrations were much lower in fructose-perfused than in glucose-perfused intestines of neonatal rats. Changes in NaPi-2b mRNA abundance by sugars were accompanied by similar changes in NaPi-2b protein abundance and in rates of inorganic phosphate (Pi) uptake. OBJECTIVE We tested the hypothesis that luminal fructose regulates NaPi-2b. DESIGN We perfused into the intestine fructose, glucose, and nonmetabolizable or poorly transported glucose analogs as well as phlorizin. RESULTS NaPi-2b mRNA concentrations and Pi uptake rates in fructose-perfused intestines were approximately 30% of those in glucose and its analogs. NaPi-2b inhibition by fructose is specific because the mRNA abundance and activity of the fructose transporter GLUT5 (glucose transporter 5) increased with fructose perfusion, whereas those of other transporters were independent of the perfusate. Plasma Pi after 4 h of perfusion was independent of the perfusate, probably because normal kidneys can maintain normophosphatemia. Inhibiting glucose-6-phosphatase, another fructose-responsive gene, with tungstate or vanadate nonspecifically inhibited NaPi-2b mRNA expression and Pi uptake in both glucose- or fructose-perfused intestines. The AMP kinase (AMPK)-activator AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) enhanced and the fatty acid synthase-AMPK inhibitor C75 (3-carboxy-4-octyl-2-methylenebutyrolactone trans-4-carboxy-5-octyl-3-methylenebutyrolactone) prevented fructose inhibition of NaPi-2b but had no effect on expression of other transporters. NaPi-2b expression decreased markedly with age and was inhibited by fructose in all age groups. CONCLUSIONS Energy levels in enterocytes may play a role in NaPi-2b inhibition by luminal fructose. Consumption of fructose that supplies approximately 10% of caloric intake by Americans clearly affects absorption of Pi and may promote Pi homeostasis in patients with impaired renal function.
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Affiliation(s)
- Séverine Kirchner
- Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103-2714, USA
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Douard V, Cui XL, Soteropoulos P, Ferraris RP. Dexamethasone sensitizes the neonatal intestine to fructose induction of intestinal fructose transporter (Slc2A5) function. Endocrinology 2008; 149:409-23. [PMID: 17947353 PMCID: PMC2194616 DOI: 10.1210/en.2007-0906] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The recent dramatic increase in fructose consumption is tightly correlated with an equally dramatic surge in the incidence of type 2 diabetes and obesity in children, but little is known about dietary fructose metabolism and absorption in neonates. The expression of the rat intestinal fructose transporter GLUT5 [Slc2A5, a member of the glucose transporter family (GLUT)] can be specifically induced by its substrate fructose, but only after weaning begins at 14 d of age. In suckling rats younger than 14 d old, dietary fructose cannot enhance GLUT5 expression. The aim of this study was to identify the mechanisms allowing fructose to stimulate GLUT5 during weaning. After intestines were perfused with fructose or glucose (control), using microarray hybridization we showed that of 5K genes analyzed in 10-d-old pups, only 13 were fructose responsive. Previous work found approximately 50 fructose-responsive genes in 20-d-old pups. To identify fructose-responsive genes whose expression also changed with age, intestines of 10- and 20-d-old littermate pups perfused with fructose were compared by microarray. Intestines of 10- and 20-d-old pups perfused with glucose were used to segregate age- but not fructose-responsive genes. About 28 genes were up- and 22 down-regulated in 20- relative to 10-d-old pups, under conditions of fructose perfusion, and many were found, by cluster analysis, to be regulated by corticosterone. When dexamethasone was injected into suckling pups before fructose perfusion, the expression of GLUT5 but not that of the sodium glucose cotransporter (SGLT) 1 and of GLUT2, as well as the uptake of fructose but not of glucose increased dramatically. Thus, dexamethasone, which allows dietary fructose to precociously stimulate intestinal fructose absorption, can mimic the effect of age and modify developmental timing mechanisms regulating GLUT5.
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Affiliation(s)
- Veronique Douard
- Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Colston JT, de la Rosa SD, Koehler M, Gonzales K, Mestril R, Freeman GL, Bailey SR, Chandrasekar B. Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor. Am J Physiol Heart Circ Physiol 2007; 293:H1839-46. [PMID: 17616748 DOI: 10.1152/ajpheart.00428.2007] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Wnt1-induced secreted protein-1 (WISP-1) is a member of the cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed (CCN) family of growth factors and is expressed in the heart at low basal levels. The purpose of this study was to investigate whether WISP-1 is upregulated in postinfarct myocardium and whether WISP-1 exerts prohypertrophic and mitogenic effects stimulating myocyte hypertrophy, cardiac fibroblast (CF) proliferation, and collagen expression. Male C57Bl/6 (25 g) mice underwent permanent occlusion of the left anterior descending coronary artery. mRNA and protein levels were analyzed by Northern and Western blot analyses. Cardiomyocyte hypertrophy was quantified by protein and DNA synthesis. CF proliferation was quantified by CyQuant assay, and soluble collagen release by Sircol assay. A time-dependent increase in WISP-1 expression was detected in vivo in the noninfarct zone of the left ventricle, which peaked at 24 h (3.1-fold, P < 0.01). Similarly, biglycan expression was increased by 3.71-fold (P < 0.01). IL-1beta and TNF-alpha expression preceded WISP-1 expression in vivo and stimulated WISP-1 expression in neonatal rat ventricular myocytes in vitro. WISP-1-induced cardiomyocyte hypertrophy was evidenced by increased protein (2.78-fold), but not DNA synthesis, and enhanced Akt phosphorylation and activity. Treatment of primary CF with WISP-1 significantly stimulated proliferation at 48 h (6,966 +/- 264 vs. 5,476 +/- 307 cells/well, P < 0.01) and enhanced collagen release by 72 h (18.4 +/- 3.1 vs. 8.4 +/- 1.0 ng/cell, P < 0.01). Our results demonstrate for the first time that WISP-1 and biglycan are upregulated in the noninfarcted myocardium in vivo, suggesting a positive amplification of WISP-1 signaling. WISP-1 stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and ECM expression in vitro. These results suggest that WISP-1 may play a critical role in post-myocardial infarction remodeling.
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Affiliation(s)
- J T Colston
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Mochizuki K, Sakaguchi N, Goda T. Triiodothyronine (T3) and fructose coordinately enhance expression of the GLUT5 gene in the small intestine of rats during weaning period. Biosci Biotechnol Biochem 2007; 71:1345-7. [PMID: 17485832 DOI: 10.1271/bbb.70014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Jejunal GLUT5 is elevated with triiodothyronine (T(3)) during weaning of rats. A perfusion of fructose into the small intestine of T(3)-injected rats at 21 d induced expression of the GLUT5 gene, but one into that of vehicle-injected rats did not. These results suggest that T(3) and fructose coordinately enhance jejunal expression of the GLUT5 gene in rats during weaning period.
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Affiliation(s)
- Kazuki Mochizuki
- Graduate School of Nutritional and Environmental Sciences, COE Program for the Twenty-First Century, University of Shizuoka, Shizuoka, Japan
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Stuart CA, Yin D, Howell MEA, Dykes RJ, Laffan JJ, Ferrando AA. Hexose transporter mRNAs for GLUT4, GLUT5, and GLUT12 predominate in human muscle. Am J Physiol Endocrinol Metab 2006; 291:E1067-73. [PMID: 16803853 DOI: 10.1152/ajpendo.00250.2006] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In the past few years, 8 additional members of the facilitative hexose transporter family have been identified, giving a total of 14 members of the SLC2A family of membrane-bound hexose transporters. To determine which of the new hexose transporters were expressed in muscle, mRNA concentrations of 11 glucose transporters (GLUTs) were quantified and compared. RNA from muscle from 10 normal volunteers was subjected to RT-PCR. Primers were designed that amplified 78- to 241-base fragments, and cDNA standards were cloned for GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, and GAPDH. Seven of these eleven hexose transporters were detectable in normal human muscle. The rank order was GLUT4, GLUT5, GLUT12, GLUT8, GLUT11, GLUT3, and GLUT1, with corresponding concentrations of 404 +/- 49, 131 +/- 14, 33 +/- 4, 5.5 +/- 0.5, 4.1 +/- 0.4, 1.2 +/- .0.1, and 0.9 +/- 0.2 copies/ng RNA (means +/- SE), respectively, for the 10 subjects. Concentrations of mRNA for GLUT4, GLUT5, and GLUT12 were much higher than those for the remainder of the GLUTs and together accounted for 98% of the total GLUT isoform mRNA. Immunoblots of muscle homogenates verified that the respective proteins for GLUT4, GLUT5, and GLUT12 were present in normal human muscle. Immunofluorescent studies demonstrated that GLUT4 and GLUT12 were predominantly expressed in type I oxidative fibers; however, GLUT5 was expressed predominantly in type II (white) fibers.
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Affiliation(s)
- Charles A Stuart
- Department of Internal Medicine, East Tennessee State University James H. Quillen College of Medicine, Johnson City, Tennessee 37614-0622, USA.
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Abstract
Carbohydrates are an important component of the diet. The carbohydrates that we ingest range from simple monosaccharides (glucose, fructose and galactose) to disaccharides (lactose, sucrose) to complex polysaccharides. Most carbohydrates are digested by salivary and pancreatic amylases, and are further broken down into monosaccharides by enzymes in the brush border membrane (BBM) of enterocytes. For example, lactase-phloridzin hydrolase and sucrase-isomaltase are two disaccharidases involved in the hydrolysis of nutritionally important disaccharides. Once monosaccharides are presented to the BBM, mature enterocytes expressing nutrient transporters transport the sugars into the enterocytes. This paper reviews the early studies that contributed to the development of a working model of intestinal sugar transport, and details the recent advances made in understanding the process by which sugars are absorbed in the intestine.
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Affiliation(s)
- Laurie A Drozdowski
- Division of Gastroenterology, Department of Medicine, University of Alberta, 5150 Dentistry Pharmacy Building, Edmonton, Alberta T6G 2N8, Canada.
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