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Hwang S, Park S, Kim J, Oh AR, Lee HJ, Cha JY. Role of Carbohydrate response element-binding protein in mediating dexamethasone-induced glucose transporter 5 expression in Caco-2BBE cells and during the developmental phase in mice. Anim Cells Syst (Seoul) 2024; 28:15-24. [PMID: 38192641 PMCID: PMC10773644 DOI: 10.1080/19768354.2023.2301009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 12/27/2023] [Indexed: 01/10/2024] Open
Abstract
Glucose transporter 5 (GLUT5), the main fructose transporter in mammals, is primarily responsible for absorbing dietary fructose in the small intestine. The expression of this intestinal gene significantly increases in response to developmental and dietary cues that reach the glucocorticoid receptor and carbohydrate response element-binding protein (ChREBP), respectively. Our study demonstrates that ChREBP is involved in the dexamethasone (Dex)-induced expression of GLUT5 in Caco-2BBE cells and the small intestine of both wild-type and ChREBP-knockout mice. Dex, a glucocorticoid, demonstrated an increase in GLUT5 mRNA levels in a dose- and time-dependent manner. While the overexpression of ChREBP moderately increased GLUT5 expression, its synergistic increase in the presence of Dex was noteworthy, whereas the suppression of ChREBP significantly reduced Dex-induced GLUT5 expression. Dex did not increase ChREBP protein levels but facilitated its nuclear translocation, thereby increasing the activity of the GLUT5 promoter. In vivo experiments conducted on 14-day-old mice pups treated with Dex for three days revealed that only wild-type mice (not ChREBP-knockout mice) exhibited Dex-mediated Glut5 gene induction, which further supports the role of ChREBP in regulating GLUT5 expression. Collectively, our results provide insights into the molecular mechanisms involved in the regulation of GLUT5 expression in response to developmental and dietary signals mediated by glucocorticoids and ChREBP. General significance: The transcription factor ChREBP is important for Dex-mediated Glut5 gene expression in the small intestine.
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Affiliation(s)
- Soonjae Hwang
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Sangbin Park
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
| | - Jaewan Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
| | - Ah-Reum Oh
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
| | - Ho-Jae Lee
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
| | - Ji-Young Cha
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
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2
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Song A, Mao Y, Wei H. GLUT5: structure, functions, diseases and potential applications. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1519-1538. [PMID: 37674366 PMCID: PMC10582729 DOI: 10.3724/abbs.2023158] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 05/19/2023] [Indexed: 09/08/2023] Open
Abstract
Glucose transporter 5 (GLUT5) is a membrane transporter that specifically transports fructose and plays a key role in dietary fructose uptake and metabolism. In recent years, a high fructose diet has occupied an important position in the daily intake of human beings, resulting in a significant increase in the incidence of obesity and metabolic diseases worldwide. Over the past few decades, GLUT5 has been well understood to play a significant role in the pathogenesis of human digestive diseases. Recently, the role of GLUT5 in human cancer has received widespread attention, and a large number of studies have focused on exploring the effects of changes in GLUT5 expression levels on cancer cell survival, metabolism and metastasis. However, due to various difficulties and shortcomings, the molecular structure and mechanism of GLUT5 have not been fully elucidated, which to some extent prevents us from revealing the relationship between GLUT5 expression and cell carcinogenesis at the protein molecular level. In this review, we summarize the current understanding of the structure and function of mammalian GLUT5 and its relationship to intestinal diseases and cancer and suggest that GLUT5 may be an important target for cancer therapy.
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Affiliation(s)
- Aqian Song
- Department of GastroenterologyBeijing Ditan HospitalCapital Medical UniversityBeijing100015China
| | - Yuanpeng Mao
- Department of GastroenterologyPeking University Ditan Teaching HospitalBeijing100015China
| | - Hongshan Wei
- Department of GastroenterologyBeijing Ditan HospitalCapital Medical UniversityBeijing100015China
- Department of GastroenterologyPeking University Ditan Teaching HospitalBeijing100015China
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3
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Comparative Effects of Allulose, Fructose, and Glucose on the Small Intestine. Nutrients 2022; 14:nu14153230. [PMID: 35956407 PMCID: PMC9370476 DOI: 10.3390/nu14153230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
Despite numerous studies on the health benefits of the rare sugar allulose, its effects on intestinal mucosal morphology and function are unclear. We therefore first determined its acute effects on the small intestinal transcriptome using DNA microarray analysis following intestinal allulose, fructose and glucose perfusion in rats. Expression levels of about 8-fold more genes were altered by allulose compared to fructose and glucose perfusion, suggesting a much greater impact on the intestinal transcriptome. Subsequent pathway analysis indicated that nutrient transport, metabolism, and digestive system development were markedly upregulated, suggesting allulose may acutely stimulate these functions. We then evaluated whether allulose can restore rat small intestinal structure and function when ingested orally following total parenteral nutrition (TPN). We also monitored allulose effects on blood levels of glucagon-like peptides (GLP) 1 and 2 in TPN rats and normal mice. Expression levels of fatty acid binding and gut barrier proteins were reduced by TPN but rescued by allulose ingestion, and paralleled GLP-2 secretion potentially acting as the mechanism mediating the rescue effect. Thus, allulose can potentially enhance disrupted gut mucosal barriers as it can more extensively modulate the intestinal transcriptome relative to glucose and fructose considered risk factors of metabolic disease.
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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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Pereira GA, Sodré FS, Murata GM, Amaral AG, Payolla TB, Campos CV, Sato FT, Anhê GF, Bordin S. Fructose Consumption by Adult Rats Exposed to Dexamethasone In Utero Changes the Phenotype of Intestinal Epithelial Cells and Exacerbates Intestinal Gluconeogenesis. Nutrients 2020; 12:nu12103062. [PMID: 33036430 PMCID: PMC7600908 DOI: 10.3390/nu12103062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 01/02/2023] Open
Abstract
Fructose consumption by rodents modulates both hepatic and intestinal lipid metabolism and gluconeogenesis. We have previously demonstrated that in utero exposure to dexamethasone (DEX) interacts with fructose consumption during adult life to exacerbate hepatic steatosis in rats. The aim of this study was to clarify if adult rats born to DEX-treated mothers would display differences in intestinal gluconeogenesis after excessive fructose intake. To address this issue, female Wistar rats were treated with DEX during pregnancy and control (CTL) mothers were kept untreated. Adult offspring born to CTL and DEX-treated mothers were assigned to receive either tap water (Control-Standard Chow (CTL-SC) and Dexamethasone-Standard Chow (DEX-SC)) or 10% fructose in the drinking water (CTL-fructose and DEX-fructose). Fructose consumption lasted for 80 days. All rats were subjected to a 40 h fasting before sample collection. We found that DEX-fructose rats have increased glucose and reduced lactate in the portal blood. Jejunum samples of DEX-fructose rats have enhanced phosphoenolpyruvate carboxykinase (PEPCK) expression and activity, higher facilitated glucose transporter member 2 (GLUT2) and facilitated glucose transporter member 5 (GLUT5) content, and increased villous height, crypt depth, and proliferating cell nuclear antigen (PCNA) staining. The current data reveal that rats born to DEX-treated mothers that consume fructose during adult life have increased intestinal gluconeogenesis while recapitulating metabolic and morphological features of the neonatal jejunum phenotype.
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Affiliation(s)
- Gizela A. Pereira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
| | - Frhancielly S. Sodré
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
| | - Gilson M. Murata
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
| | - Andressa G. Amaral
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
| | - Tanyara B. Payolla
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
| | - Carolina V. Campos
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, 13083-887 SP, Brazil; (C.V.C.); (G.F.A.)
| | - Fabio T. Sato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
| | - Gabriel F. Anhê
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, 13083-887 SP, Brazil; (C.V.C.); (G.F.A.)
| | - Silvana Bordin
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP, Brazil; (G.A.P.); (F.S.S.); (G.M.M.); (A.G.A.); (T.B.P.); (F.T.S.)
- Correspondence: ; Tel.: +55-11-3091-7245
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Trotta RJ, Ward AK, Swanson KC. Influence of dietary fructose supplementation on visceral organ mass, carbohydrase activity, and mRNA expression of genes involved in small intestinal carbohydrate assimilation in neonatal calves. J Dairy Sci 2020; 103:10060-10073. [PMID: 32921447 DOI: 10.3168/jds.2020-18145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 06/29/2020] [Indexed: 01/18/2023]
Abstract
The hypothesis of this experiment was that dietary fructose would influence visceral organ mass, carbohydrase activity, and mRNA expression of carbohydrases and nutrient transporters in the small intestine in neonatal calves. Therefore, our objective was to use the neonatal calf as a model to evaluate the effects of postruminal fructose supply on small intestinal carbohydrate assimilation. Ten calves (<7 d of age; 41.2 ± 1.46 kg of body weight) were fed milk replacer at 2.0% of body weight daily (816 ± 90.5 g/d; 272 ± 30.1 g/L; dry-matter basis) in 2 equal portions and assigned to the following dietary treatment groups: (1) milk replacer (control; n = 6) or (2) milk replacer + 2.2 g of fructose/kg of body weight (fructose; n = 4). Calves were fed dietary treatments for 28 d, with jugular blood sampled every 7 d before and after the morning feeding. Calves were slaughtered, and visceral weights were recorded. Postruminal carbohydrase activities were assayed. Quantitative real-time PCR was conducted for small intestinal mRNA expression of nutrient transporters [solute carrier family 2 member 5 (GLUT5), solute carrier family 2 member 2 (GLUT2), and solute carrier family 5 member 1 (SGLT1)], carbohydrases (lactase, maltase-glucoamylase, and sucrase-isomaltase), and ketohexokinase (KHK). Data were analyzed using MIXED procedures in SAS version 9.4 (SAS Institute Inc, Cary, NC). Dietary fructose supplementation decreased serum glucose concentration. Small intestinal mass was greater in calves supplemented with fructose. Dietary fructose supplementation did not influence pancreatic α-amylase, small intestinal isomaltase, or maltase activities. Sucrase activity was undetected in the small intestine. Dietary fructose supplementation increased small intestinal glucoamylase activity per gram of tissue by 30% and increased maltase-glucoamylase mRNA expression by 6.8-fold. Dietary fructose supplementation did not influence mRNA expression of GLUT5, SGLT1, GLUT2, or KHK. Dietary fructose supplementation increased small intestinal lactase mRNA expression by 3.1-fold. Sucrase-isomaltase mRNA expression in the small intestine decreased 5.1-fold with dietary fructose supplementation. Dietary fructose supplementation does not induce sucrase activity in neonatal calves; however, sucrase-isomaltase may be transcriptionally regulated by dietary fructose in neonatal calves. More research is needed to compare glucose and fructose at isocaloric intakes to examine effects of dietary fructose at equal metabolizable energy intake.
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Affiliation(s)
- Ronald J Trotta
- Department of Animal Sciences, North Dakota State University, Fargo 58108
| | - Alison K Ward
- Department of Animal Sciences, North Dakota State University, Fargo 58108
| | - Kendall C Swanson
- Department of Animal Sciences, North Dakota State University, Fargo 58108.
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7
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Abstract
Irritable bowel syndrome (IBS) is a chronic disorder characterised by recurrent abdominal pain or discomfort and transit disturbances with heterogeneous pathophysiological mechanisms. The link between food and gastrointestinal (GI) symptoms is often reported by patients with IBS and the role of fructose has recently been highlighted. Fructose malabsorption can easily be assessed by hydrogen and/or methane breath test in response to 25 g fructose; and its prevalence is about 22 % in patients with IBS. The mechanism of fructose-related symptoms is incompletely understood. Osmotic load, fermentation and visceral hypersensitivity are likely to participate in GI symptoms in the IBS population and may be triggered or worsened by fructose. A low-fructose diet could be integrated in the overall treatment strategy, but its role and implication in the improvement of IBS symptoms should be evaluated. In the present review, we discuss fructose malabsorption in adult patients with IBS and the interest of a low-fructose diet in order to underline the important role of fructose in IBS.
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8
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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: 71] [Impact Index Per Article: 11.8] [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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Li H, Cheng J, Yuan Y, Luo R, Zhu Z. Age-related intestinal monosaccharides transporters expression and villus surface area increase in broiler and layer chickens. J Anim Physiol Anim Nutr (Berl) 2019; 104:144-155. [PMID: 31556184 DOI: 10.1111/jpn.13211] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 07/27/2019] [Accepted: 08/23/2019] [Indexed: 11/27/2022]
Abstract
In the chicken small intestine, glucose is mainly transported by the apically located sodium/glucose cotransporter 1 (SGLT1) and the basolaterally located glucose transporter 2 (GLUT2). Fructose is transported by the apically located glucose transporter 5 (GLUT5) and similarly by GLUT2. During the early post-hatching period, the intestinal villus surface area (VSA) should be considered as an important factor related to the monosaccharide absorption capacity. Our objective here was to study intestinal monosaccharide absorption by analyzing the effects of age, diet, and breed on monosaccharide transporters and the VSA. The mRNA expression patterns of SGLT1, GLUT2 and GLUT5 genes in broiler and layer chickens were measured from the day of hatching to day 28 using the absolute quantitative real-time PCR. Both the intestinal mRNA expression levels of these genes and the VSA were affected by age. The mRNA expression levels of SGLT1 and GLUT2 were significantly increased from day 1 to day 3 and then decreased from day 3 to day 28. The expression levels of GLUT5 decreased from day 1 to day 7. The broiler chickens VSAs were significantly larger than those of the layer chickens from days 7 to 28. The effect of diet on the gene expression patterns of these monosaccharide transporters and the VSA were not significant. Our results suggest that the expression levels of these monosaccharide transporters are increased rapidly at the beginning of intestinal growth to meet the demands for monosaccharides to support the fast growth of the chick before day 7. As intestinal maturation and VSA increased, the expression levels of these monosaccharide genes decreased to a certain expression level to maintain the intestinal transport capacity and the absorption balance of all other nutrients.
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Affiliation(s)
- Huifeng Li
- Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Shanxi, China
| | - Jin Cheng
- Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Shanxi, China
| | - Yitong Yuan
- Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Shanxi, China
| | - Rong Luo
- Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Shanxi, China
| | - Zhiwei Zhu
- Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Shanxi, China
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10
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Payolla TB, Teixeira CJ, Sato FT, Murata GM, Zonta GA, Sodré FS, Campos CV, Mesquita FN, Anhê GF, Bordin S. In Utero Dexamethasone Exposure Exacerbates Hepatic Steatosis in Rats That Consume Fructose During Adulthood. Nutrients 2019; 11:nu11092114. [PMID: 31491968 PMCID: PMC6770256 DOI: 10.3390/nu11092114] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/10/2019] [Accepted: 08/21/2019] [Indexed: 12/12/2022] Open
Abstract
Distinct environmental insults might interact with fructose consumption and contribute to the development of metabolic disorders. To address whether in utero glucocorticoid exposure and fructose intake modulate metabolic responses, adult female Wistar rats were exposed to dexamethasone (DEX) during pregnancy, and the offspring were administered fructose at a later time. Briefly, dams received DEX during the third period of pregnancy, while control dams remained untreated. Offspring born to control and DEX-treated mothers were defined as CTL-off and DEX-off, respectively, while untreated animals were designated CTL-off-CTL and DEX-off-CTL. CLT-off and DEX-off treated with 10% fructose in the drinking water for 8 weeks are referred to as CTL-off-FRU and DEX-off-FRU. We found that fructose promoted glucose intolerance and whole-body gluconeogenesis in both CTL-off-FRU and DEX-off-FRU animals. On the other hand, hepatic lipid accumulation was significantly stimulated in DEX-off-FRU rats when compared to the CTL-off-FRU group. The DEX-off-FRU group also displayed impaired very-low-density lipoprotein (VLDL) production and reduced hepatic expression of apoB, mttp, and sec22b. DEX-off-FRU has lower hepatic levels of autophagy markers. Taken together, our results support the unprecedented notion that in utero glucocorticoid exposure exacerbates hepatic steatosis caused by fructose consumption later in life.
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Affiliation(s)
- Tanyara B Payolla
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Caio J Teixeira
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-887, Brazil
| | - Fabio T Sato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Gilson M Murata
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Gizela A Zonta
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Frhancielly S Sodré
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Carolina V Campos
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Filiphe N Mesquita
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-887, Brazil
| | - Gabriel F Anhê
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Sao Paulo 13083-887, Brazil
| | - Silvana Bordin
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.
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11
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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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12
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Merigo F, Brandolese A, Facchin S, Missaggia S, Bernardi P, Boschi F, D’Incà R, Savarino EV, Sbarbati A, Sturniolo GC. Glucose transporter expression in the human colon. World J Gastroenterol 2018; 24:775-793. [PMID: 29467549 PMCID: PMC5807937 DOI: 10.3748/wjg.v24.i7.775] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 12/13/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate by immunostaining glucose transporter expression in human colorectal mucosa in controls and patients with inflammatory bowel disease (IBD).
METHODS Colorectal samples were obtained from patients undergoing lower endoscopic colonoscopy or recto-sigmoidoscopy. Patients diagnosed with ulcerative colitis (n = 18) or Crohn’s disease (n = 10) and scheduled for diagnostic colonoscopy were enrolled. Patients who underwent colonoscopy for prevention screening of colorectal cancer or were followed-up after polypectomy or had a history of lower gastrointestinal symptoms were designated as the control group (CTRL, n = 16). Inflammatory status of the mucosa at the sampling site was evaluated histologically and/or endoscopically. A total of 147 biopsies of colorectal mucosa were collected and processed for immunohistochemistry analysis. The expression of GLUT2, SGLT1, and GLUT5 glucose transporters was investigated using immunoperoxidase labeling. To compare immunoreactivity of GLUT5 and LYVE-1, which is a marker for lymphatic vessel endothelium, double-labeled confocal microscopy was used.
RESULTS Immunohistochemical analysis revealed that GLUT2, SGLT1, and GLUT5 were expressed only in short epithelial portions of the large intestinal mucosa. No important differences were observed in glucose transporter expression between the samples obtained from the different portions of the colorectal tract and between the different patient groups. Unexpectedly, GLUT5 expression was also identified in vessels, mainly concentrated in specific areas where the vessels were clustered. Immunostaining with LYVE-1 and GLUT5 antibodies revealed that GLUT5-immunoreactive (-IR) clusters of vessels were concentrated in areas internal to those that were LYVE-1 positive. GLUT5 and LYVE-1 did not appear to be colocalized but rather showed a close topographical relationship on the endothelium. Based on their LYVE-1 expression, GLUT5-IR vessels were identified as lymphatic. Both inflamed and non-inflamed mucosal colorectal tissue biopsies from the IBD and CTRL patients showed GLUT5-IR clusters of lymphatic vessels.
CONCLUSION Glucose transporter immunoreactivity is present in colorectal mucosa in controls and IBD patients. GLUT5 expression is also associated with lymphatic vessels. This novel finding aids in the characterization of lymphatic vasculature in IBD patients.
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Affiliation(s)
- Flavia Merigo
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Alessandro Brandolese
- Department of Medicine, Gastroenterology Section, University of Verona, Verona I-37134, Italy
| | - Sonia Facchin
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
| | - Silvia Missaggia
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Paolo Bernardi
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Federico Boschi
- Department of Computer Science, University of Verona, Verona I-37134, Italy
| | - Renata D’Incà
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
| | - Andrea Sbarbati
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
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Wang Y, Dellatore P, Douard V, Qin L, Watford M, Ferraris RP, Lin T, Shapses SA. High fat diet enriched with saturated, but not monounsaturated fatty acids adversely affects femur, and both diets increase calcium absorption in older female mice. Nutr Res 2016; 36:742-50. [PMID: 27262536 PMCID: PMC4919156 DOI: 10.1016/j.nutres.2016.03.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/28/2016] [Accepted: 03/01/2016] [Indexed: 02/06/2023]
Abstract
Diet induced obesity has been shown to reduce bone mineral density (BMD) and Ca absorption. However, previous experiments have not examined the effect of high fat diet (HFD) in the absence of obesity or addressed the type of dietary fatty acids. The primary objective of this study was to determine the effects of different types of high fat feeding, without obesity, on fractional calcium absorption (FCA) and bone health. It was hypothesized that dietary fat would increase FCA and reduce BMD. Mature 8-month-old female C57BL/6J mice were fed one of three diets: a HFD (45% fat) enriched either with monounsaturated fatty acids (MUFAs) or with saturated fatty acids (SFAs), and a normal fat diet (NFD; 10% fat). Food consumption was controlled to achieve a similar body weight gain in all groups. After 8wk, total body bone mineral content and BMD as well as femur total and cortical volumetric BMD were lower in SFA compared with NFD groups (P<.05). In contrast, femoral trabecular bone was not affected by the SFAs, whereas MUFAs increased trabecular volume fraction and thickness. The rise over time in FCA was greater in mice fed HFD than NFD and final FCA was higher with HFD (P<.05). Intestinal calbindin-D9k gene and hepatic cytochrome P450 2r1 protein levels were higher with the MUFA than the NFD diet (P<.05). In conclusion, HFDs elevated FCA overtime; however, an adverse effect of HFD on bone was only observed in the SFA group, while MUFAs show neutral or beneficial effects.
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Affiliation(s)
- Yang Wang
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Peter Dellatore
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Veronique Douard
- Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, USA
| | - Ling Qin
- Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Malcolm Watford
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Ronaldo P Ferraris
- Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, USA
| | - Tiao Lin
- Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA; Department of Orthopedic Surgery, First Affiliated Hospital of Sun Yat-sen University, No,58 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Sue A Shapses
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA.
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Inamochi Y, Dey A, Nishiyama A, Kubota T, Ozato K, Goda T, Mochizuki K. Transcription elongation factor Brd4-P-TEFb accelerates intestinal differentiation-associated SLC2A5 gene expression. Biochem Biophys Rep 2016; 7:150-156. [PMID: 28955901 PMCID: PMC5613281 DOI: 10.1016/j.bbrep.2016.05.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/04/2016] [Accepted: 05/23/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Expression of the fructose transporter gene SLC2A5 and histone acetylation in the transcribed region are induced by differentiation associated-signals such as glucocorticoids and p44/42 mitogen-activated protein kinase (MAPK) inhibition in small intestinal Caco-2 cells. METHODS We co-treated with glucocorticoid receptor agonist dexamethasone (Dex) and p44/42 MAPK inhibitor PD98059 (PD) in Caco-2 cells with or without Brd4 small hairpin (sh) RNA expression vector, and the cells were analyzed by qRT-PCR and chromatin immunoprecipitation assays. The small intestine of wild-type mice and Brd4+/- mice during weaning period were analyzed by qRT-PCR. RESULTS Co-treatment with Dex and PD increased binding of the bromodomain-containing protein-4 (Brd4)-positive transcriptional elongation factor-b (P-TEFb)-RNA polymerase II complex to acetylated histones in the transcribed region of SLC2A5. Brd4-protein depletion by shRNA revealed that the association of these proteins on the transcribed region of SLC2A5 promoted gene expression in a Brd4-dependent manner. Expression of small-intestine Slc2a5, but not another intestinal gene sucrase-isomaltase, during weaning period, was significantly lower in Brd4+/- mice compared with wild-type mice. CONCLUSIONS Brd4-P-TEFb plays a crucial role in differentiation-associated transcription of SLC2A5 gene in intestinal Caco-2 cells and in the small intestine of mice during weaning period. GENERAL SIGNIFICANCE Histone acetylation and the transcription elongation factor Brd4 are important for SLC2A5 expression in the small intestine.
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Affiliation(s)
- Yuko Inamochi
- Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences and Global COE, Laboratory of Nutritional Physiology, University of Shizuoka, Shizuoka, Japan
| | - Anup Dey
- Laboratory of Molecular Growth Regulation, NICHD, NIH, Bethesda, MD, USA
| | - Akira Nishiyama
- Laboratory of Molecular Growth Regulation, NICHD, NIH, Bethesda, MD, USA
| | - Takeo Kubota
- Division of Engineering, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Keiko Ozato
- Laboratory of Molecular Growth Regulation, NICHD, NIH, Bethesda, MD, USA
| | - Toshinao Goda
- Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences and Global COE, Laboratory of Nutritional Physiology, University of Shizuoka, Shizuoka, Japan
| | - Kazuki Mochizuki
- Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences and Global COE, Laboratory of Nutritional Physiology, University of Shizuoka, Shizuoka, Japan.,Laboratory of Food and Nutritional Sciences, Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan
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15
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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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16
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Glucocorticoids suppress GLP-1 secretion: possible contribution to their diabetogenic effects. Clin Sci (Lond) 2015; 129:405-14. [PMID: 25853863 DOI: 10.1042/cs20140719] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 04/08/2015] [Indexed: 12/23/2022]
Abstract
Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum- and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion.
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Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Götze O, Verrey F. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids 2014; 47:693-705. [DOI: 10.1007/s00726-014-1889-6] [Citation(s) in RCA: 229] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 12/03/2014] [Indexed: 02/06/2023]
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18
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Douard V, Patel C, Lee J, Tharabenjasin P, Williams E, Fritton JC, Sabbagh Y, Ferraris RP. Chronic high fructose intake reduces serum 1,25 (OH)2D3 levels in calcium-sufficient rodents. PLoS One 2014; 9:e93611. [PMID: 24718641 PMCID: PMC3981704 DOI: 10.1371/journal.pone.0093611] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 03/05/2014] [Indexed: 12/14/2022] Open
Abstract
Excessive fructose consumption inhibits adaptive increases in intestinal Ca2+ transport in lactating and weanling rats with increased Ca2+ requirements by preventing the increase in serum levels of 1,25(OH)2D3. Here we tested the hypothesis that chronic fructose intake decreases 1,25(OH)2D3 levels independent of increases in Ca2+ requirements. Adult mice fed for five wk a high glucose-low Ca2+ diet displayed expected compensatory increases in intestinal and renal Ca2+ transporter expression and activity, in renal CYP27B1 (coding for 1α-hydroxylase) expression as well as in serum 1,25(OH)2D3 levels, compared with mice fed isocaloric glucose- or fructose-normal Ca2+ diets. Replacing glucose with fructose prevented these increases in Ca2+ transporter, CYP27B1, and 1,25(OH)2D3 levels induced by a low Ca2+ diet. In adult mice fed for three mo a normal Ca2+ diet, renal expression of CYP27B1 and of CYP24A1 (24-hydroxylase) decreased and increased, respectively, when the carbohydrate source was fructose instead of glucose or starch. Intestinal and renal Ca2+ transporter activity and expression did not vary with dietary carbohydrate. To determine the time course of fructose effects, a high fructose or glucose diet with normal Ca2+ levels was fed to adult rats for three mo. Serum levels of 1,25(OH)2D3 decreased and of FGF23 increased significantly over time. Renal expression of CYP27B1 and serum levels of 1,25(OH)2D3 still decreased in fructose- compared to those in glucose-fed rats after three mo. Serum parathyroid hormone, Ca2+ and phosphate levels were normal and independent of dietary sugar as well as time of feeding. Thus, chronically high fructose intakes can decrease serum levels of 1,25(OH)2D3 in adult rodents experiencing no Ca2+ stress and fed sufficient levels of dietary Ca2+. This finding is highly significant because fructose constitutes a substantial portion of the average diet of Americans already deficient in vitamin D.
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Affiliation(s)
- Veronique Douard
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers Biomedical and Health Sciences (RBHS), Newark, New Jersey, United States of America
- * E-mail:
| | - Chirag Patel
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers Biomedical and Health Sciences (RBHS), Newark, New Jersey, United States of America
| | - Jacklyn Lee
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers Biomedical and Health Sciences (RBHS), Newark, New Jersey, United States of America
| | - Phuntila Tharabenjasin
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers Biomedical and Health Sciences (RBHS), Newark, New Jersey, United States of America
| | - Edek Williams
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - J. Christopher Fritton
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
- Department of Orthopaedics, New Jersey Medical School, RBHS, Newark, New Jersey, United States of America
| | - Yves Sabbagh
- Tissue Protection and Repair, Sanofi-Genzyme R&D Center, Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America
| | - Ronaldo P. Ferraris
- Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers Biomedical and Health Sciences (RBHS), Newark, New Jersey, United States of America
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19
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Fructose promotes the differentiation of 3T3-L1 adipocytes and accelerates lipid metabolism. FEBS Lett 2013; 588:490-6. [DOI: 10.1016/j.febslet.2013.12.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/04/2013] [Accepted: 12/07/2013] [Indexed: 01/20/2023]
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20
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Walker RW, Lê KA, Davis J, Alderete TL, Cherry R, Lebel S, Goran MI. High rates of fructose malabsorption are associated with reduced liver fat in obese African Americans. J Am Coll Nutr 2013; 31:369-74. [PMID: 23529994 DOI: 10.1080/07315724.2012.10720445] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE African Americans commonly have lower liver fat accumulation than Hispanics, despite a similar propensity for obesity. Both ethnicities exhibit high consumption of fructose-containing beverages, which has been associated with high liver fat owing to the lipogenic properties of fructose. Therefore, differences in fructose absorption may be an important factor in regulating liver fat deposition. We hypothesized that fructose malabsorption in African Americans may reduce hepatic delivery of fructose, thus contributing to lower liver fat deposition compared to Hispanics. METHODS Thirty-seven obese young adults aged 21.4 ± 2.1 years (16 African American, 21 Hispanic) underwent a 3-hour hydrogen (H2) breath test to assess fructose malabsorption. Magnetic resonance imaging was used to determine visceral and subcutaneous adipose tissue volume and liver fat. Fructose malabsorption was expressed as an area under the curve for H2 production (H2 AUC). RESULTS Compared to Hispanics, African Americans had lower liver fat (5.4% ± 5.0% vs 8.9% ± 2.3%, p = 0.02) and a higher prevalence of fructose malabsorption (75.0% vs 42.9%; p = 0.05). Liver fat was negatively related to the extent of fructose malabsorption in African Americans (r = -0.53, p = 0.03), and this relationship was independent of the volumes of total fat and subcutaneous and visceral adipose tissue. There were no significant relationships between liver fat and fructose malabsorption in Hispanics. CONCLUSION African Americans have both a higher prevalence and a greater magnitude of fructose malabsorption than Hispanics. In African Americans, fructose malabsorption was negatively correlated with liver fat, which may be protective against fatty liver disease.
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Affiliation(s)
- Ryan W Walker
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
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21
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Asmerom Y, Slater L, Boskovic DS, Bahjri K, Plank MS, Phillips R, Deming D, Ashwal S, Fayard E, Angeles DM. Oral sucrose for heel lance increases adenosine triphosphate use and oxidative stress in preterm neonates. J Pediatr 2013; 163:29-35.e1. [PMID: 23415615 PMCID: PMC3687041 DOI: 10.1016/j.jpeds.2012.12.088] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Revised: 10/30/2012] [Accepted: 12/27/2012] [Indexed: 01/30/2023]
Abstract
OBJECTIVE To examine the effects of sucrose on pain and biochemical markers of adenosine triphosphate (ATP) degradation and oxidative stress in preterm neonates experiencing a clinically required heel lance. STUDY DESIGN Preterm neonates that met study criteria (n = 131) were randomized into 3 groups: (1) control; (2) heel lance treated with placebo and non-nutritive sucking; and (3) heel lance treated with sucrose and non-nutritive sucking. Plasma markers of ATP degradation (hypoxanthine, xanthine, and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured with the Premature Infant Pain Profile. Data were analyzed by the use of repeated-measures ANOVA and Spearman rho. RESULTS We found significant increases in plasma hypoxanthine and uric acid over time in neonates who received sucrose. We also found a significant negative correlation between pain scores and plasma allantoin concentration in a subgroup of neonates who received sucrose. CONCLUSION A single dose of oral sucrose, given before heel lance, significantly increased ATP use and oxidative stress in premature neonates. Because neonates are given multiple doses of sucrose per day, randomized trials are needed to examine the effects of repeated sucrose administration on ATP degradation, oxidative stress, and cell injury.
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Affiliation(s)
- Yayesh Asmerom
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Laurel Slater
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Danilo S. Boskovic
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Khaled Bahjri
- Departments of Biostatistics, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Megan S Plank
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Raylene Phillips
- Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Douglas Deming
- Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Stephen Ashwal
- Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Elba Fayard
- Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350
| | - Danilyn M. Angeles
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350
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Douard V, Sabbagh Y, Lee J, Patel C, Kemp FW, Bogden JD, Lin S, Ferraris RP. Excessive fructose intake causes 1,25-(OH)(2)D(3)-dependent inhibition of intestinal and renal calcium transport in growing rats. Am J Physiol Endocrinol Metab 2013; 304:E1303-13. [PMID: 23571713 PMCID: PMC3680696 DOI: 10.1152/ajpendo.00582.2012] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca(2+) transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca(2+) absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca(2+) transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca(2+) transport rate as well as in expression of intestinal and renal Ca(2+) transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca(2+) transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca(2+) transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca(2+) and vitamin D deficiency.
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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
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Douard V, Ferraris RP. The role of fructose transporters in diseases linked to excessive fructose intake. J Physiol 2012; 591:401-14. [PMID: 23129794 DOI: 10.1113/jphysiol.2011.215731] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Fructose intake has increased dramatically since humans were hunter-gatherers, probably outpacing the capacity of human evolution to make physiologically healthy adaptations. Epidemiological data indicate that this increasing trend continued until recently. Excessive intakes that chronically increase portal and peripheral blood fructose concentrations to >1 and 0.1 mm, respectively, are now associated with numerous diseases and syndromes. The role of the fructose transporters GLUT5 and GLUT2 in causing, contributing to or exacerbating these diseases is not well known. GLUT5 expression seems extremely low in neonatal intestines, and limited absorptive capacities for fructose may explain the high incidence of malabsorption in infants and cause problems in adults unable to upregulate GLUT5 levels to match fructose concentrations in the diet. GLUT5- and GLUT2-mediated fructose effects on intestinal electrolyte transporters, hepatic uric acid metabolism, as well as renal and cardiomyocyte function, may play a role in fructose-induced hypertension. Likewise, GLUT2 may contribute to the development of non-alcoholic fatty liver disease by facilitating the uptake of fructose. Finally, GLUT5 may play a role in the atypical growth of certain cancers and fat tissues. We also highlight research areas that should yield information needed to better understand the role of these GLUTs in fructose-induced diseases.
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Affiliation(s)
- Veronique Douard
- Department of Pharmacology & Physiology, UMDNJ – New Jersey Medical School, 185 S. Orange Avenue, Newark, NJ 07101-1749, USA
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Nader N, Ng SSM, Wang Y, Abel BS, Chrousos GP, Kino T. Liver x receptors regulate the transcriptional activity of the glucocorticoid receptor: implications for the carbohydrate metabolism. PLoS One 2012; 7:e26751. [PMID: 22457708 PMCID: PMC3310817 DOI: 10.1371/journal.pone.0026751] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Accepted: 10/03/2011] [Indexed: 01/26/2023] Open
Abstract
GLUCOCORTICOIDS are steroid hormones that strongly influence intermediary carbohydrate metabolism by increasing the transcription rate of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, and suppress the immune system through the glucocorticoid receptor (GR). The liver X receptors (LXRs), on the other hand, bind to cholesterol metabolites, heterodimerize with the retinoid X receptor (RXR), and regulate the cholesterol turnover, the hepatic glucose metabolism by decreasing the expression of G6Pase, and repress a set of inflammatory genes in immune cells. Since the actions of these receptors overlap with each other, we evaluated the crosstalk between the GR- and LXR-mediated signaling systems. Transient transfection-based reporter assays and gene silencing methods using siRNAs for LXRs showed that overexpression/ligand (GW3965) activation of LXRs/RXRs repressed GR-stimulated transactivation of certain glucocorticoid response element (GRE)-driven promoters in a gene-specific fashion. Activation of LXRs by GW3965 attenuated dexamethasone-stimulated elevation of circulating glucose in rats. It also suppressed dexamethasone-induced mRNA expression of hepatic glucose-6-phosphatase (G6Pase) in rats, mice and human hepatoma HepG2 cells, whereas endogenous, unliganded LXRs were required for dexamethasone-induced mRNA expression of phosphoenolpyruvate carboxylase. In microarray transcriptomic analysis of rat liver, GW3965 differentially regulated glucocorticoid-induced transcriptional activity of about 15% of endogenous glucocorticoid-responsive genes. To examine the mechanism through which activated LXRs attenuated GR transcriptional activity, we examined LXRα/RXRα binding to GREs. Endogenous LXRα/RXRα bound GREs and inhibited GR binding to these DNA sequences both in in vitro and in vivo chromatin immunoprecipitation assays, while their recombinant proteins did so on classic or G6Pase GREs in gel mobility shift assays. We propose that administration of LXR agonists may be beneficial in glucocorticoid treatment- or stress-associated dysmetabolic states by directly and gene-specifically attenuating the transcriptional activity of the GR on glucose and/or lipid metabolism.
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Affiliation(s)
- Nancy Nader
- Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
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Yoshinaga Y, Mochizuki K, Goda T. Trimethylation of histone H3K4 is associated with the induction of fructose-inducible genes in rat jejunum. Biochem Biophys Res Commun 2012; 419:605-11. [PMID: 22366086 DOI: 10.1016/j.bbrc.2012.02.043] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2012] [Accepted: 02/07/2012] [Indexed: 11/24/2022]
Abstract
We previously reported that fructose force-feeding rapidly induces jejunal Slc2a5 gene expression in rats. In this study, we conducted microarray analyses using total RNA to identify genes upregulated in rat jejunum by fructose force-feeding. Rats were force-fed fructose, glucose or distilled water for 6h. Genes such as Slc2a5, Cdkn1c, Cabp2, Ranbp3, Vwce and Gcgr were induced by force-feeding with fructose compared with glucose or distilled water. Chromatin immunoprecipitation assays revealed that trimethylation of histone H3K4, and acetylation of histones H3 and H4, on the transcribed region of these fructose-inducible genes were enhanced by force-feeding of fructose, but not glucose or distilled water. These results suggest that the induction of genes in the rat jejunum by fructose force-feeding is coordinately regulated by histone modifications, particularly trimethylation of histone H3K4.
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Affiliation(s)
- Yumiko Yoshinaga
- Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences and Global COE Program, The University of Shizuoka, Suruga-ku, Shizuoka-shi, Shizuoka 422-8526, Japan
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26
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Raja M, Puntheeranurak T, Hinterdorfer P, Kinne R. SLC5 and SLC2 transporters in epithelia-cellular role and molecular mechanisms. CURRENT TOPICS IN MEMBRANES 2012. [PMID: 23177983 DOI: 10.1016/b978-0-12-394316-3.00002-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Members of the SLC5 and SLC2 family are prominently involved in epithelial sugar transport. SGLT1 (sodium-glucose transporter) and SGLT2, as representatives of the former, mediate sodium-dependent uptake of sugars into intestinal and renal cells. GLUT2 (glucose transporter), as representative of the latter, facilitates the sodium-independent exit of sugars from cells. SGLT has played a major role in the formulation and experimental proof for the existence of sodium cotransport systems. Based on the sequence data and biochemical and biophysical analyses, the role of extramembranous loops in sugar and inhibitor binding can be delineated. Crystal structures and homology modeling of SGLT reveal that the sugar translocation involves operation of two hydrophobic gates and intermediate exofacial and endofacial occluded states of the carrier in an alternating access model. The same basic model is proposed for GLUT1. Studies on GLUT1 have pioneered the isolation of eukaryotic transporters by biochemical methods and the development of transport kinetics and transporter models. For GLUT1, results from extensive mutagenesis, cysteine substitution and accessibility studies can be incorporated into a homology model with a barrel-like structure in which accessibility to the extracellular and intracellular medium is altered by pinching movements of some of the helices. For SGLT1 and GLUT1, the extensive hydrophilic and hydrophobic interactions between sugars and binding sites of the various intramembrane helices occur and lead to different substrate specificities and inhibitor affinities of the two transporters. A complex network of regulatory steps adapts the transport activity to the needs of the body.
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Affiliation(s)
- Mobeen Raja
- Max Planck Institute of Molecular Physiology, Dortmund, Germany
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Douard V, Suzuki T, Sabbagh Y, Lee J, Shapses S, Lin S, Ferraris RP. Dietary fructose inhibits lactation-induced adaptations in rat 1,25-(OH)₂D₃ synthesis and calcium transport. FASEB J 2011; 26:707-21. [PMID: 22038050 DOI: 10.1096/fj.11-190264] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
We recently showed that excessive fructose consumption, already associated with numerous metabolic abnormalities, reduces rates of intestinal Ca(2+) transport. Using a rat lactation model with increased Ca(2+) requirements, we tested the hypothesis that mechanisms underlying these inhibitory effects of fructose involve reductions in renal synthesis of 1,25-(OH)(2)D(3). Pregnant and virgin (control) rats were fed isocaloric fructose or, as controls, glucose, and starch diets from d 2 of gestation to the end of lactation. Compared to virgins, lactating dams fed glucose or starch had higher rates of intestinal transcellular Ca(2+) transport, elevated intestinal and renal expression of Ca(2+) channels, Ca(2+)-binding proteins, and CaATPases, as well as increased levels of 25-(OH)D(3) and 1,25-(OH)(2)D(3). Fructose consumption prevented almost all of these lactation-induced increases, and reduced vitamin D receptor binding to promoter regions of Ca(2+) channels and binding proteins. Changes in 1,25-(OH)(2)D(3) level were tightly correlated with alterations in expression of 1α-hydroxylase but not with levels of parathyroid hormone and of 24-hydroxylase. Bone mineral density, content, and mechanical strength each decreased with lactation, but then fructose exacerbated these effects. When Ca(2+) requirements increase during lactation or similar physiologically challenging conditions, excessive fructose consumption may perturb Ca(2+) homeostasis because of fructose-induced reductions in synthesis of 1,25-(OH)(2)D(3).
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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, NJ 07101-1709, USA
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Intestinal gene expression in pigs: effects of reduced feed intake during weaning and potential impact of dietary components. Nutr Res Rev 2011; 24:155-75. [DOI: 10.1017/s0954422411000047] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The weaning transition is characterised by morphological, histological and microbial changes, often leading to weaning-associated disorders. These intestinal changes can partly be ascribed to the lack of luminal nutrition arising from the reduced feed intake common in pigs after weaning. It is increasingly becoming clear that changes in the supply with enteral nutrients may have major impacts on intestinal gene expression. Furthermore, the major dietary constituents, i.e. carbohydrates, fatty acids and amino acids, participate in the regulation of intestinal gene expression. However, nutrients may also escape digestion by mammalian enzymes in the upper gastrointestinal tract. These nutrients can be used by the microflora, resulting in the production of bacterial metabolites, for example, SCFA, which may affect intestinal gene expression indirectly. The present review provides an insight on possible effects of reduced feed intake on intestinal gene expression, as it may occur post-weaning. Detailed knowledge on effects of reduced feed intake on intestinal gene expression may help to understand weaning-associated intestinal dysfunctions and diseases. Examples are given of intestinal genes which may be altered in their expression due to supply with specific nutrients. In that way, gene expression could be modulated by dietary means, thereby acting as a potential therapeutic tool. This could be achieved, for example, by influencing genes coding for digestive or absorptive proteins, thus optimising digestive function and metabolism, but also with regard to immune response, or by influencing proliferative processes, thereby enhancing mucosal repair. This would be of special interest when designing a diet to overcome weaning-associated problems.
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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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Boudry G, David ES, Douard V, Monteiro IM, Le Huërou-Luron I, Ferraris RP. Role of intestinal transporters in neonatal nutrition: carbohydrates, proteins, lipids, minerals, and vitamins. J Pediatr Gastroenterol Nutr 2010; 51:380-401. [PMID: 20808244 DOI: 10.1097/mpg.0b013e3181eb5ad6] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
To support rapid growth and a high metabolic rate, infants require enormous amounts of nutrients. The small intestine must have the complete array of transporters that absorb the nutrients released from digested food. Failure of intestinal transporters to function properly often presents symptoms as "failure to thrive" because nutrients are not absorbed and as diarrhea because unabsorbed nutrients upset luminal osmolality or become substrates of intestinal bacteria. We enumerate the nutrients that constitute human milk and various infant milk formulas, explain their importance in neonatal nutrition, then describe for each nutrient the transporter(s) that absorbs it from the intestinal lumen into the enterocyte cytosol and from the cytosol to the portal blood. More than 100 membrane and cytosolic transporters are now thought to facilitate absorption of minerals and vitamins as well as products of digestion of the macronutrients carbohydrates, proteins, and lipids. We highlight research areas that should yield information needed to better understand the important role of these transporters during normal development.
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Affiliation(s)
- Gaëlle Boudry
- Institut National de Recherche Agronomique, UMR1079 Système d'Elevage, Nutrition, Animale et Humaine, St-Gilles, France
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Douard V, Asgerally A, Sabbagh Y, Sugiura S, Shapses SA, Casirola D, Ferraris RP. Dietary fructose inhibits intestinal calcium absorption and induces vitamin D insufficiency in CKD. J Am Soc Nephrol 2009; 21:261-71. [PMID: 19959720 DOI: 10.1681/asn.2009080795] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.
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Affiliation(s)
- Veronique Douard
- Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, Newark, NJ 07101-1709, 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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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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