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Fujii W, Yamazaki O, Hirohama D, Kaseda K, Kuribayashi-Okuma E, Tsuji M, Hosoyamada M, Kochi Y, Shibata S. Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12. J Clin Invest 2025; 135:e186633. [PMID: 40100301 PMCID: PMC12077893 DOI: 10.1172/jci186633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 03/12/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUNDHyperinsulinemia and insulin resistance often accompany elevated serum urate levels (hyperuricemia), a highly heritable condition that triggers gout; however, the underlying mechanisms are unclear.METHODSWe evaluated the association between the index of hyperinsulinemia and the fractional excretion of urate (FEUA) in 162 outpatients. The underlying mechanisms were investigated through single-cell data analysis and kinase screening combined with cell culture experiments. In 377,358 participants of the UK Biobank (UKBB), we analyzed serum urate, hyperinsulinemia, and salt intake. We also examined gene-environment interactions using single nucleotide variants in SLC22A12, which encodes urate transporter 1 (URAT1).RESULTSThe index of hyperinsulinemia was inversely associated with FEUA independently of other covariates. Mechanistically, URAT1 cell-surface abundance and urate transport activity were regulated by URAT1-Thr408 phosphorylation, which was stimulated by hyperinsulinemia via AKT. Kinase screening and single-cell data analysis revealed that serum and glucocorticoid-regulated kinase 1 (SGK1), induced by high salt, activated the same pathway, increasing URAT1. Arg405 was essential for these kinases to phosphorylate URAT1-Thr408. In UKBB participants, hyperinsulinemia and high salt intake were independently associated with increased serum urate levels. We found that SLC22A12 expression quantitative trait locus (eQTL) rs475688 synergistically enhanced the positive association between serum urate and hyperinsulinemia.CONCLUSIONURAT1 mediates the association between hyperinsulinemia and hyperuricemia. Our data provide evidence for the role of gene-environment interactions in determining serum urate levels, paving the way for personalized management of hyperuricemia.FUNDINGACRO Research Grants of Teikyo University; Japan Society for the Promotion of Science; the Japanese Society of Gout and Uric & Nucleic Acids; Fuji Yakuhin; Nanken-Kyoten; Medical Research Center Initiative for High Depth Omics.
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Affiliation(s)
- Wataru Fujii
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
- Department of Genomic Function and Diversity, Medical Research Laboratory, Institute for Integrated Research, Institute of Science Tokyo, Tokyo, Japan
| | - Osamu Yamazaki
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Daigoro Hirohama
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Ken Kaseda
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Emiko Kuribayashi-Okuma
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | | | - Makoto Hosoyamada
- Laboratory of Human Physiology and Pathology, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan
| | - Yuta Kochi
- Department of Genomic Function and Diversity, Medical Research Laboratory, Institute for Integrated Research, Institute of Science Tokyo, Tokyo, Japan
| | - Shigeru Shibata
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
- Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan
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Matsushita D, Toyoda Y, Lee Y, Aoi M, Matsuo H, Takada T, Nishizawa T. Structural basis of urate transport by glucose transporter 9. Cell Rep 2025; 44:115514. [PMID: 40186864 DOI: 10.1016/j.celrep.2025.115514] [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: 09/04/2024] [Revised: 01/17/2025] [Accepted: 03/13/2025] [Indexed: 04/07/2025] Open
Abstract
Glucose transporter 9 (GLUT9) is a critical urate transporter involved in renal reabsorption, playing a pivotal role in regulating physiological urate levels and representing a potential therapeutic target for gout. Despite such clinical significance, the structural basis of urate recognition and transport by GLUT9 remains elusive. Here, we present the cryoelectron microscopy (cryo-EM) structures of GLUT9 in the inward-open conformation in both apo and urate-bound states. Urate binds in a cleft between the N-terminal and C-terminal domains, interacting via hydrogen bonds and hydrophobic interactions. Structural comparison with sugar-transporting GLUTs highlights unique amino acid compositions in the substrate recognition pocket of GLUT9. Functional and mutational studies directly measuring GLUT9-mediated urate uptake further demonstrate the cooperative roles of multiple residues in urate recognition. Our findings elucidate the structural basis of urate transport by GLUT9 and provide valuable insights for the development of uricosuric drugs targeting GLUT9.
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Affiliation(s)
- Daiki Matsushita
- Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan
| | - Yu Toyoda
- Department of Pharmacy, The University of Tokyo Hospital, Tokyo 113-8655, Japan; Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa 359-8513, Japan
| | - Yongchan Lee
- Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan
| | - Maeda Aoi
- Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan
| | - Hirotaka Matsuo
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa 359-8513, Japan
| | - Tappei Takada
- Department of Pharmacy, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Tomohiro Nishizawa
- Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan.
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Gheller JM, Silva WALD, Souza-Cáceres MB, Silva AFD, Ribeiro Ferreira MGC, Santana TDS, Dos Santos AC, Pereira-Junior SA, Nogueira É, Alencar SAD, Macedo GG, Seneda MM, Chiaratti MR, Melo-Sterza FDA. Transcriptomic analysis of heifers according to antral follicle count. Theriogenology 2025; 237:178-187. [PMID: 40024020 DOI: 10.1016/j.theriogenology.2025.02.024] [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: 10/08/2024] [Revised: 02/19/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025]
Abstract
While antral follicle count (AFC) has been associated with higher pregnancy rates, at present, our understanding of it as a reproductive parameter remains incomplete. This study aimed to characterize gene expression profile of oocytes from crossbred Bos taurus x Bos indicus heifers with high and low AFCs. Crossbred Nelore-Angus heifers (n = 50) with a mean (SD) age of 9.6 ± 0.55 months, a weight of 295.4 ± 32.6 kg, and a BCS of 3.44 ± 0.41 were studied in a feedlot system. The heifers received a hormonal protocol based on injectable progesterone and estradiol cypionate administered 12 days apart, and ovarian ultrasonography (US) was performed 12 days after to assess the AFC. Based on AFC, heifers were divided into low (≤14 follicles) and high (≥31 follicles) AFC, groups.Forty-five days after US, 14 heifers were slaughtered, and their ovaries were collected for morphological analysis and follicle aspiration. Cumulus-oocyte complexes (COCs) from the high and low AFC groups were graded according to their quality. Only best-quality COCs were stored for RNA-seq analysis. No differences were found in the presence or diameter of the dominant follicle and corpus luteum in the US, nor in the volume of the dominant follicle postmortem. The quantity of COCs recovered from high-AFC heifers was higher than that from low-AFC heifers (P < 0.05), and a tendency (P = 0.07) toward a higher amount of grade II COCs was observed. Thirty-two genes were differentially expressed between the groups, of which 30 were up-regulated and two down-regulated in the low AFC group. Among these, 22 % (7/32) were associated with fertility (CAB39, SLC2A6, CITED2, FDX1, HSD11B2, CD81, and PLA2G12B). Moreover, 9 and 2 exclusive genes were identified in the high and low AFC groups, respectively. Enrichment analyses showed that genes exclusive to oocytes from low-AFC heifers were associated with fundamental cellular processes, such as biosynthesis/biogenesis of ribosomes, peptides, amides, and nucleotides, and also with autophagy, mitophagy and mTOR signalling pathways.On the other hand, only one pathway was enriched in the high AFC group, but this cannot be related to the events studied No differences were observed in the ovarian structures after pre-synchronization of the estrus cycle of young Crossbred Nelore-Angus heifers. However, a tendency of a higher amount of grade II COCs was observed in heifers with high AFC than in those with low AFC. RNA sequencing results indicated that the main differences between high and low AFC heifers were not reflected in the genes directly related to fertility.
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Affiliation(s)
- Janaina Menegazzo Gheller
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Federal de Mato Grosso do Sul, Av. Sen. Filinto Müler, 2443 - Pioneiros, Campo Grande - MS, Brazil
| | - Wilian Aparecido Leite da Silva
- Programa de Pós-Graduação em Zootecnia, Universidade Estadual de Mato Grosso do Sul, Rodovia Graziela Maciel Barroso, Km 12 Zona Rural - Camisão, Aquidauana, MS, Brazil
| | - Mirela Brochado Souza-Cáceres
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, Rod. Washington Luís km 235, Jardim Guanabara, São Carlos, SP, Brazil
| | - Aldair Félix da Silva
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Federal de Mato Grosso do Sul, Av. Sen. Filinto Müler, 2443 - Pioneiros, Campo Grande - MS, Brazil
| | - Mariane Gabriela Cesar Ribeiro Ferreira
- Programa de Pós-Graduação em Zootecnia, Universidade Estadual de Mato Grosso do Sul, Rodovia Graziela Maciel Barroso, Km 12 Zona Rural - Camisão, Aquidauana, MS, Brazil
| | - Taynara Dos Santos Santana
- Programa de Pós-Graduação em Zootecnia, Universidade Estadual de Mato Grosso do Sul, Rodovia Graziela Maciel Barroso, Km 12 Zona Rural - Camisão, Aquidauana, MS, Brazil
| | - Angélica Camargo Dos Santos
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, Rod. Washington Luís km 235, Jardim Guanabara, São Carlos, SP, Brazil
| | - Sérgio Antonio Pereira-Junior
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, Rod. Washington Luís km 235, Jardim Guanabara, São Carlos, SP, Brazil
| | - Ériklis Nogueira
- Empresa Brasileira de Pesquisa Agropecuária - Embrapa Gado de Corte, Av. Rádio Maia, 830 - Vila Popular, Campo Grande, MS, Brazil
| | - Sérgio Amorim de Alencar
- Universidade Católica de Brasília, QS 07, Lote 01, Taguatinga Sul - Taguatinga, Brasília, DF, Brazil
| | - Gustavo Guerino Macedo
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Federal de Mato Grosso do Sul, Av. Sen. Filinto Müler, 2443 - Pioneiros, Campo Grande - MS, Brazil
| | - Marcelo Marcondes Seneda
- Universidade Estadual de Londrina, Rodovia Celso Garcia Cid, PR-445, Km 380, Londrina, PR, Brazil
| | - Marcos Roberto Chiaratti
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, Rod. Washington Luís km 235, Jardim Guanabara, São Carlos, SP, Brazil
| | - Fabiana de Andrade Melo-Sterza
- Programa de Pós-Graduação em Ciências Veterinárias, Universidade Federal de Mato Grosso do Sul, Av. Sen. Filinto Müler, 2443 - Pioneiros, Campo Grande - MS, Brazil; Programa de Pós-Graduação em Zootecnia, Universidade Estadual de Mato Grosso do Sul, Rodovia Graziela Maciel Barroso, Km 12 Zona Rural - Camisão, Aquidauana, MS, Brazil.
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Khandelwal NK, Gupta M, Kumar P, Balasubramani SG, Echeverria I, Stroud RM. Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter. Proc Natl Acad Sci U S A 2025; 122:e2418282122. [PMID: 39937868 PMCID: PMC11848319 DOI: 10.1073/pnas.2418282122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 12/10/2024] [Indexed: 02/14/2025] Open
Abstract
Urate provides ~50% of the reducing potential in human and primate plasma which is key to detoxifying reactive oxygen by-products of cellular metabolism. Urate is the endpoint of purine metabolism in primates, and its concentration in plasma is a balance between excretion from kidney and intestine, and subsequent reabsorption in and through cells of kidney proximal tubules to maintain a regulated concentration in plasma. SLC2A9 is the primary transporter that returns urate from the basolateral side of kidney tubule cells back to plasma. A shorter splice variant of SLC2A9 is directed to the apical surface where several transporters recapture urate from the tubule back into cells. Too high a concentration in plasma causes hyperuricemia, is linked to gout, and favors kidney stone formation. To understand the molecular basis of uric acid transport and the role of disease-causing mutations in SLC2A9, we determined structures of human SLC2A9 in its apo form, and its urate-bound form by cryo-EM, at resolution of 3.3 Å and 4.1 Å respectively. Both structures are captured in an inward open conformation. Using the inward-facing structure as a template we modeled the outward-facing conformation to understand the alternating access mechanism. Alternative salt bridge pairs on the cytoplasmic side suggest a mechanism that can balance the energetics of the inward open and outward open states. The location of disease-causing mutants suggests their role in impacting function. Our structures elucidate the molecular basis for urate selectivity and transport and provide a platform for future structure-based drug discovery aimed at reducing plasma urate levels in diseases of hyperuricemia and gout.
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Affiliation(s)
- Nitesh Kumar Khandelwal
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA94143
| | - Meghna Gupta
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA94143
| | - Paras Kumar
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA94143
| | - Sree Ganesh Balasubramani
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA94158
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA94158
| | - Ignacia Echeverria
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA94158
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA94158
| | - Robert M. Stroud
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA94143
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5
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Shen Z, Xu L, Wu T, Wang H, Wang Q, Ge X, Kong F, Huang G, Pan X. Structural basis for urate recognition and apigenin inhibition of human GLUT9. Nat Commun 2024; 15:5039. [PMID: 38866775 PMCID: PMC11169512 DOI: 10.1038/s41467-024-49420-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 06/03/2024] [Indexed: 06/14/2024] Open
Abstract
Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, is the primary risk factor for the development of gout. The high-capacity urate transporter GLUT9 represents a promising target for gout treatment. Here, we present cryo-electron microscopy structures of human GLUT9 in complex with urate or its inhibitor apigenin at overall resolutions of 3.5 Å and 3.3 Å, respectively. In both structures, GLUT9 exhibits an inward open conformation, wherein the substrate binding pocket faces the intracellular side. These structures unveil the molecular basis for GLUT9's substrate preference of urate over glucose, and show that apigenin acts as a competitive inhibitor by occupying the substrate binding site. Our findings provide critical information for the development of specific inhibitors targeting GLUT9 as potential therapeutics for gout and hyperuricemia.
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Affiliation(s)
- Zilin Shen
- Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Li Xu
- Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, 518107, Guangdong, China
| | - Tong Wu
- Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Huan Wang
- Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Qifan Wang
- Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Xiaofei Ge
- Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Fang Kong
- Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Gaoxingyu Huang
- Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, 310024, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, 310024, Zhejiang, China
| | - Xiaojing Pan
- Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, 518107, Guangdong, China.
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Wu S, Li C, Li Y, Liu J, Rong C, Pei H, Li X, Zeng X, Mao W. SLC2A9 rs16890979 reduces uric acid absorption by kidney organoids. Front Cell Dev Biol 2024; 11:1268226. [PMID: 38269090 PMCID: PMC10806012 DOI: 10.3389/fcell.2023.1268226] [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: 08/01/2023] [Accepted: 12/14/2023] [Indexed: 01/26/2024] Open
Abstract
Introduction: The excretion and absorption of uric acid (UA) by the kidneys helps regulate serum UA levels. GLUT9, encoded by SLC2A9, is mainly expressed in the renal tubules responsible for UA absorption. SLC2A9 polymorphisms are associated with different serum UA levels. However, the lack of proper in vitro models has stalled research on the mechanisms of single nucleotide polymorphisms (SNPs) that affect UA metabolism in human urate transporters. Methods: In this study, we constructed a gene-edited human embryonic stem cells-9 (ESC-H9) derived kidney organoid bearing rs16890979, an SLC2A9 missense mutation with undetermined associations with hyperuricemia or hypouricemia. Kidney organoids derived from ESC-H9 with genetical overexpression (OE) and low expression (shRNA) of SLC2A9 to serve as controls to study the function of SLC2A9. The function of rs16890979 on UA metabolism was evaluated after placing the organoids to urate-containing medium and following histopathological analysis. Results: The kidney organoids with heterozygous or homozygous rs16890979 mutations showed normal SLC2A9 expression levels and histological distribution, phenotypically similar to the wild-type controls. However, reduced absorption of UA by the kidney organoids with rs16890979 mutants was observed. This finding together with the observation that UA absorption is increased in organoids with SLC2A9 overexpression and decreased in those with SLC2A9 knockdown, suggest that GLUT9 is responsible for UA absorption, and the rs16890979 SNP may compromise this functionality. Moreover, epithelial-mesenchymal transition (EMT) was detected in organoids after UA treatment, especially in the kidney organoid carrying GLUT9OE, suggesting the cytobiological mechanism explaining the pathological features in hyperuricosuria-related renal injury. Discussion: This study showing the transitional value of kidney organoid modeling the function of SNPs on UA metabolism. With a defined genetic background and a confirmed UA absorption function should be useful for studies on renal histological, cellular, and molecular mechanisms with this organoid model.
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Affiliation(s)
- Shouhai Wu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Chuang Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, China
| | - Yizhen Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junyi Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Cuiping Rong
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongfei Pei
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Xiong Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiang Zeng
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Lab of Stem Cell Biology and Innovative Research of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine/Guangdong Academy of Chinese Medicine, Guangzhou, China
- National Institute for Stem Cell Clinical Research, Guangdong Provincial Hospital of Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Mao
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, China
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
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Ichida K. [Uric Acid Metabolism, Uric Acid Transporters and Dysuricemia]. YAKUGAKU ZASSHI 2024; 144:659-674. [PMID: 38825475 DOI: 10.1248/yakushi.23-00217] [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] [Indexed: 06/04/2024]
Abstract
Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.
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MESH Headings
- Humans
- Hyperuricemia/etiology
- Hyperuricemia/metabolism
- Hyperuricemia/genetics
- Uric Acid/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Organic Anion Transporters/metabolism
- Organic Anion Transporters/genetics
- Glucose Transport Proteins, Facilitative/metabolism
- Glucose Transport Proteins, Facilitative/genetics
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Xanthine Dehydrogenase/metabolism
- Xanthine Dehydrogenase/genetics
- Xanthine Dehydrogenase/deficiency
- Animals
- Organic Cation Transport Proteins/genetics
- Organic Cation Transport Proteins/metabolism
- Renal Tubular Transport, Inborn Errors/genetics
- Renal Tubular Transport, Inborn Errors/etiology
- Renal Tubular Transport, Inborn Errors/metabolism
- Urinary Calculi/etiology
- Urinary Calculi/metabolism
- Urinary Calculi/genetics
- Metabolism, Inborn Errors
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Affiliation(s)
- Kimiyoshi Ichida
- Department of Pathophysiology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
- Division of Kidney and Hypertension, The Jikei University School of Medicine
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Zhou J, Zhang M, Xie Q, Xu N, Li M, Zhang M, Hao C. Recurrent exercise-induced acute kidney injury associated with hypouricemia: a case report and literature review. BMC Nephrol 2023; 24:384. [PMID: 38129773 PMCID: PMC10740252 DOI: 10.1186/s12882-023-03378-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 10/26/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene. CASE PRESENTATION A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 μmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene. CONCLUSIONS This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.
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Affiliation(s)
- Jie Zhou
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
- Department of Nephrology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Min Zhang
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
| | - Qionghong Xie
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ningxin Xu
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Mingxin Li
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ming Zhang
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuanming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
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9
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Kim JH, Yang HJ, Park S, Lee HJ, Song YS. Differential Gene Expression in the Penile Cavernosum of Streptozotocin-Induced Diabetic Rats. Int Neurourol J 2023; 27:234-242. [PMID: 38171323 PMCID: PMC10762368 DOI: 10.5213/inj.2346074.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/01/2023] [Indexed: 01/05/2024] Open
Abstract
PURPOSE Men with diabetes mellitus (DM) often present with severe erectile dysfunction (ED). This ED is less responsive to current pharmacological therapies. If we know the upregulated or downregulated genes of diabetic ED, we can inhibit or enhance the expression of such genes through RNA or gene overexpression. METHODS To investigate gene changes associated with ED in type 1 DM, we examined the alterations of gene expression in the cavernosum of streptozotocin-induced diabetic rats. Specifically, we considered 11,636 genes (9,623 upregulated and 2,013 downregulated) to be differentially expressed in the diabetic rat cavernosum group (n=4) compared to the control group (n=4). The analysis of differentially expressed genes using the gene ontology (GO) classification indicated that the following were enriched: downregulated genes such as cell cycle, extracellular matrix, glycosylphosphatidylinositol-anchor biosynthesis and upregulated genes such as calcium signaling, neurotrophin signaling, apoptosis, arginine and proline metabolism, gap junction, transforming growth factor-β signaling, tight junction, vascular smooth muscle contraction, and vascular endothelial growth factor (VEGF) signaling. We examined a more than 2-fold upregulated or downregulated change in expression, using real time polymerase chain reaction. Analysis of differentially expressed genes, using the GO classification, indicated the enrichment. RESULTS Of the 41,105 genes initially considered, statistical filtering of the array analysis showed 9,623 upregulated genes and 2,013 downregulated genes with at least 2-fold changes in expression (P<0.05). With Bonferroni correction, SLC2A9 (solute carrier family 2 member 9), LRRC20 (leucine rick repeat containing 20), PLK1 (polo like kinase 1), and AATK (apoptosis-associated tyrosine kinase) were all 2-fold changed genes. CONCLUSION This study broadens the scope of candidate genes that may be relevant to the pathophysiology of diabetic ED. In particular, their enhancement or inhibition could represent a novel treatment for diabetic ED.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, Korea
| | - Hee Jo Yang
- Department of Urology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University School of Medicine, Cheonan, Korea
| | - Suyeon Park
- Department of Biostatistics, Soonchunhyang University School of Medicine, Seoul, Korea
| | - Hong Jun Lee
- College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea
- Research Institute, e-biogen Inc., Seoul, Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, Korea
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10
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Perdomo-Ramírez A, Ramos-Trujillo E, Claverie-Martín F. New SLC22A12 (URAT1) Variant Associated with Renal Hypouricemia Identified by Whole-Exome Sequencing Analysis and Bioinformatics Predictions. Genes (Basel) 2023; 14:1823. [PMID: 37761963 PMCID: PMC10530539 DOI: 10.3390/genes14091823] [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: 07/29/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings.
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Affiliation(s)
- Ana Perdomo-Ramírez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (A.P.-R.); (E.R.-T.)
| | - Elena Ramos-Trujillo
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (A.P.-R.); (E.R.-T.)
- Departamento de Medicina Física y Farmacología, Facultad de Ciencias de la Salud, Sección Medicina, Universidad de La Laguna, 38071 Santa Cruz de Tenerife, Spain
| | - Félix Claverie-Martín
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (A.P.-R.); (E.R.-T.)
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11
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Perdomo-Ramirez A, Cordoba-Lanus E, Trujillo-Frias CJ, Gonzalez-Navasa C, Ramos-Trujillo E, Luis-Yanes MI, Garcia-Nieto V, Claverie-Martin F. Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M). Int J Mol Sci 2023; 24:ijms24098455. [PMID: 37176161 PMCID: PMC10179447 DOI: 10.3390/ijms24098455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/02/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect.
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Affiliation(s)
- Ana Perdomo-Ramirez
- Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Elizabeth Cordoba-Lanus
- Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Instituto Universitario de Enfermedades Tropicales y Salud Publica de Canarias (IUETSPC), Universidad de La Laguna, 38296 Santa Cruz de Tenerife, Spain
| | - Carmen Jane Trujillo-Frias
- Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Carolina Gonzalez-Navasa
- Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Seccion Medicina, Departamento de Medicina Fisica y Farmacologia, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain
| | - Elena Ramos-Trujillo
- Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Seccion Medicina, Departamento de Medicina Fisica y Farmacologia, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain
| | - Maria Isabel Luis-Yanes
- Unidad de Nefrologia Pediatrica, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Victor Garcia-Nieto
- Unidad de Nefrologia Pediatrica, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Felix Claverie-Martin
- Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
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12
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Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice. Cells 2022; 11:cells11223703. [PMID: 36429132 PMCID: PMC9688737 DOI: 10.3390/cells11223703] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 11/23/2022] Open
Abstract
Hyperuricemia is a common feature in pregnancies compromised by pre-eclampsia, a pregnancy disease characterized by hypertension and proteinuria. The role of uric acid in the pathogenesis of pre-eclampsia remains largely unclear. The aim of this study was to investigate the effect of elevated uric acid serum levels during pregnancy on maternal blood pressure and neonatal outcome using two different murine knockout models. Non-pregnant liver-specific GLUT9 knockout (LG9KO) mice showed elevated uric acid serum concentrations but no hypertensive blood pressure levels. During pregnancy, however, blood pressure levels of these animals increased in the second and third trimester, and circadian blood pressure dipping was severely altered when compared to non-pregnant LG9KO mice. The impact of hyperuricemia on fetal development was investigated using a systemic GLUT9 knockout (G9KO) mouse model. Fetal hyperuricemia caused distinctive renal tissue injuries and, subsequently an impaired neonatal growth pattern. These findings provide strong evidence that hyperuricemia plays a major role in the pathogenesis of hypertensive pregnancy disorders such as pre-eclampsia. These novel insights may enable the development of preventive and therapeutic strategies for hyperuricemia-related diseases.
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13
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Temre MK, Kumar A, Singh SM. An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors. Front Pharmacol 2022; 13:1035510. [PMID: 36386187 PMCID: PMC9663470 DOI: 10.3389/fphar.2022.1035510] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/18/2022] [Indexed: 07/23/2023] Open
Abstract
Neoplastic cells displayed altered metabolism with accelerated glycolysis. Therefore, these cells need a mammoth supply of glucose for which they display an upregulated expression of various glucose transporters (GLUT). Thus, novel antineoplastic strategies focus on inhibiting GLUT to intersect the glycolytic lifeline of cancer cells. This review focuses on the current status of various GLUT inhibition scenarios. The GLUT inhibitors belong to both natural and synthetic small inhibitory molecules category. As neoplastic cells express multiple GLUT isoforms, it is necessary to use pan-GLUT inhibitors. Nevertheless, it is also necessary that such pan-GLUT inhibitors exert their action at a low concentration so that normal healthy cells are left unharmed and minimal injury is caused to the other vital organs and systems of the body. Moreover, approaches are also emerging from combining GLUT inhibitors with other chemotherapeutic agents to potentiate the antineoplastic action. A new pan-GLUT inhibitor named glutor, a piperazine-one derivative, has shown a potent antineoplastic action owing to its inhibitory action exerted at nanomolar concentrations. The review discusses the merits and limitations of the existing GLUT inhibitory approach with possible future outcomes.
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Affiliation(s)
- Mithlesh Kumar Temre
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ajay Kumar
- Deparment of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
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14
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Jiang Z, Cao J, Su H, Cao H, Sun Z, Jiang H, Fan Y. Exercise serum regulates uric acid transporters in normal rat kidney cells. Sci Rep 2022; 12:18086. [PMID: 36302802 PMCID: PMC9613886 DOI: 10.1038/s41598-022-22570-w] [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: 07/01/2022] [Accepted: 10/17/2022] [Indexed: 12/30/2022] Open
Abstract
Hyperuricemia (HUA) refers to a physiological condition of high serum uric acid (SUA) level in the body, which may cause an increased risk of several chronic diseases. The kidney's impaired uric acid (UA) metabolism is an important reason for HUA. In this study, we tested the hypothesis that circulating factors produced during exercise regulate the expression of ABCC4, ABCG2, URAT1, and GLUT9 in normal rat kidneys and normal rat kidney cells (NRK-52E) and their relationship with NF-κB and NRF-2. NRK-52E cells were separately cultured by serum from 10 healthy SD rats who did not exercise (CON) and 10 healthy SD rats who did aerobic treadmill exercise for 6 weeks. Cells cultured by serum from rats who did aerobic treadmill exercise for 6 weeks were separated by without NRF-2 inhibitor (EXE) and with NRF-2 inhibitor (EXE + ML). SUA level of rats was tested by using dry chemical assays, xanthine oxidase (XOD) activity in serum and liver were tested by using enzyme colorimetry assays, protein expression in kidney and NRK-52E cells were tested by using Western-blot, and UA levels in the upper or lower chamber were tested by colorimetry assays. Aerobic exercise reduced SUA levels in rats but did not significantly affect on liver xanthine oxidase. It also increased the expression of some UA transporters in the kidney and NRK-52E cells and increased the cells' ability in UA excretion. When the NRF-2 was inhibited, the NF-κB and ABCG2 increased, and the expression of ABCC4, URAT1, and GLUT9 decreased. In conclusion, this study suggested that 6 weeks of aerobic treadmill exercise intervention may help to improve the excretion of UA in renal cells, suggesting that long-term aerobic exercise may be a means to prevent hyperuricemia.
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Affiliation(s)
- Zhongye Jiang
- grid.411614.70000 0001 2223 5394Sport Biochemistry Department, Sport Science College, Beijing Sport University, Beijing, China
| | - Jianmin Cao
- grid.411614.70000 0001 2223 5394Sport Biochemistry Department, Sport Science College, Beijing Sport University, Beijing, China
| | - Hao Su
- grid.411614.70000 0001 2223 5394Sport Biochemistry Department, Sport Science College, Beijing Sport University, Beijing, China
| | - Hui Cao
- grid.261049.80000 0004 0645 4572North China Electric Power University, Beijing, China
| | - Zeyuan Sun
- grid.411614.70000 0001 2223 5394Sport Biochemistry Department, Sport Science College, Beijing Sport University, Beijing, China
| | - Haoze Jiang
- grid.411614.70000 0001 2223 5394Sport Biochemistry Department, Sport Science College, Beijing Sport University, Beijing, China
| | - Yanjun Fan
- grid.411614.70000 0001 2223 5394Sport Biochemistry Department, Sport Science College, Beijing Sport University, Beijing, China
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15
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Crawley WT, Jungels CG, Stenmark KR, Fini MA. U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia. Redox Biol 2022; 51:102271. [PMID: 35228125 PMCID: PMC8889273 DOI: 10.1016/j.redox.2022.102271] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 12/12/2022] Open
Abstract
Serum uric acid (SUA) is significantly elevated in obesity, gout, type 2 diabetes mellitus, and the metabolic syndrome and appears to contribute to the renal, cardiovascular and pulmonary comorbidities that are associated with these disorders. Most previous studies have focused on the pathophysiologic effects of high levels of uric acid (hyperuricemia). More recently, research has also shifted to the impact of hypouricemia, with multiple studies showing the potentially damaging effects that can be caused by abnormally low levels of SUA. Along with these observations, recent inconclusive data from human studies evaluating the treatment of hyperuricemia with xanthine oxidoreductase (XOR) inhibitors have added to the debate about the causal role of UA in human disease processes. SUA, which is largely derived from hepatic degradation of purines, appears to exert both systemic pro-inflammatory effects that contribute to disease and protective antioxidant properties. XOR, which catalyzes the terminal two steps of purine degradation, is the major source of both reactive oxygen species (O2.-, H2O2) and UA. This review will summarize the evidence that both elevated and low SUA may be risk factors for renal, cardiovascular and pulmonary comorbidities. It will also discuss the mechanisms through which modulation of either XOR activity or SUA may contribute to vascular redox hemostasis. We will address future research studies to better account for the differential effects of high versus low SUA in the hope that this will identify new evidence-based approaches for the management of hyperuricemia.
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Affiliation(s)
- William T Crawley
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA
| | - Cyprien G Jungels
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA
| | - Kurt R Stenmark
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA; Division of Pulmonary and Critical Care, Department of Pediatrics, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA
| | - Mehdi A Fini
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA; Division of Pulmonary and Critical Care, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA.
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16
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Glucose Transporter 9 (GLUT9) Plays an Important Role in the Placental Uric Acid Transport System. Cells 2022; 11:cells11040633. [PMID: 35203284 PMCID: PMC8870656 DOI: 10.3390/cells11040633] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/30/2022] [Accepted: 02/08/2022] [Indexed: 01/09/2023] Open
Abstract
Background: Hyperuricemia is a common laboratory finding in pregnant women compromised by preeclampsia. A growing body of evidence suggests that uric acid is involved in the pathogenesis of preeclampsia. Glucose transporter 9 (GLUT9) is a high-capacity uric acid transporter. The aim of this study was to investigate the placental uric acid transport system, and to identify the (sub-) cellular localization of GLUT9. Methods: Specific antibodies against GLUT9a and GLUT9b isoforms were raised, and human villous (placental) tissue was immunohistochemically stained. A systemic GLUT9 knockout (G9KO) mouse model was used to assess the placental uric acid transport capacity by measurements of uric acid serum levels in the fetal and maternal circulation. Results: GLUT9a and GLUT9b co-localized with the villous (apical) membrane, but not with the basal membrane, of the syncytiotrophoblast. Fetal and maternal uric acid serum levels were closely correlated. G9KO fetuses showed substantially higher uric acid serum concentrations than their mothers. Conclusions: These findings demonstrate that the placenta efficiently maintains uric acid homeostasis, and that GLUT9 plays a key role in the placental uric acid transport system, at least in this murine model. Further studies investigating the role of the placental uric acid transport system in preeclampsia are eagerly needed.
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17
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Tin A, Schlosser P, Matias-Garcia PR, Thio CHL, Joehanes R, Liu H, Yu Z, Weihs A, Hoppmann A, Grundner-Culemann F, Min JL, Kuhns VLH, Adeyemo AA, Agyemang C, Ärnlöv J, Aziz NA, Baccarelli A, Bochud M, Brenner H, Bressler J, Breteler MMB, Carmeli C, Chaker L, Coresh J, Corre T, Correa A, Cox SR, Delgado GE, Eckardt KU, Ekici AB, Endlich K, Floyd JS, Fraszczyk E, Gao X, Gào X, Gelber AC, Ghanbari M, Ghasemi S, Gieger C, Greenland P, Grove ML, Harris SE, Hemani G, Henneman P, Herder C, Horvath S, Hou L, Hurme MA, Hwang SJ, Kardia SLR, Kasela S, Kleber ME, Koenig W, Kooner JS, Kronenberg F, Kühnel B, Ladd-Acosta C, Lehtimäki T, Lind L, Liu D, Lloyd-Jones DM, Lorkowski S, Lu AT, Marioni RE, März W, McCartney DL, Meeks KAC, Milani L, Mishra PP, Nauck M, Nowak C, Peters A, Prokisch H, Psaty BM, Raitakari OT, Ratliff SM, Reiner AP, Schöttker B, Schwartz J, Sedaghat S, Smith JA, Sotoodehnia N, Stocker HR, Stringhini S, Sundström J, Swenson BR, van Meurs JBJ, van Vliet-Ostaptchouk JV, Venema A, Völker U, Winkelmann J, Wolffenbuttel BHR, Zhao W, Zheng Y, Loh M, Snieder H, Waldenberger M, Levy D, Akilesh S, Woodward OM, et alTin A, Schlosser P, Matias-Garcia PR, Thio CHL, Joehanes R, Liu H, Yu Z, Weihs A, Hoppmann A, Grundner-Culemann F, Min JL, Kuhns VLH, Adeyemo AA, Agyemang C, Ärnlöv J, Aziz NA, Baccarelli A, Bochud M, Brenner H, Bressler J, Breteler MMB, Carmeli C, Chaker L, Coresh J, Corre T, Correa A, Cox SR, Delgado GE, Eckardt KU, Ekici AB, Endlich K, Floyd JS, Fraszczyk E, Gao X, Gào X, Gelber AC, Ghanbari M, Ghasemi S, Gieger C, Greenland P, Grove ML, Harris SE, Hemani G, Henneman P, Herder C, Horvath S, Hou L, Hurme MA, Hwang SJ, Kardia SLR, Kasela S, Kleber ME, Koenig W, Kooner JS, Kronenberg F, Kühnel B, Ladd-Acosta C, Lehtimäki T, Lind L, Liu D, Lloyd-Jones DM, Lorkowski S, Lu AT, Marioni RE, März W, McCartney DL, Meeks KAC, Milani L, Mishra PP, Nauck M, Nowak C, Peters A, Prokisch H, Psaty BM, Raitakari OT, Ratliff SM, Reiner AP, Schöttker B, Schwartz J, Sedaghat S, Smith JA, Sotoodehnia N, Stocker HR, Stringhini S, Sundström J, Swenson BR, van Meurs JBJ, van Vliet-Ostaptchouk JV, Venema A, Völker U, Winkelmann J, Wolffenbuttel BHR, Zhao W, Zheng Y, Loh M, Snieder H, Waldenberger M, Levy D, Akilesh S, Woodward OM, Susztak K, Teumer A, Köttgen A. Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. Nat Commun 2021; 12:7173. [PMID: 34887389 PMCID: PMC8660809 DOI: 10.1038/s41467-021-27198-4] [Show More Authors] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 11/08/2021] [Indexed: 12/25/2022] Open
Abstract
Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
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Affiliation(s)
- Adrienne Tin
- Department of Medicine, University of Mississippi Medical Center, Jackson, 39216, MS, USA.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
| | - Pascal Schlosser
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Pamela R Matias-Garcia
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Chris H L Thio
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Roby Joehanes
- Framingham Heart Study, Framingham, MA, USA
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hongbo Liu
- Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, PA, USA
| | - Zhi Yu
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Antoine Weihs
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Anselm Hoppmann
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Franziska Grundner-Culemann
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Josine L Min
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | | | - Adebowale A Adeyemo
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Charles Agyemang
- Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, the Netherlands
| | - Johan Ärnlöv
- Department of Neurobiology, Care Sciences and Society (NVS), Family Medicine and Primary Care Unit, Karolinska Institutet, Huddinge, Sweden
- School of Health and Social Studies, Dalarna University, Falun, Sweden
| | - Nasir A Aziz
- Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Neurology, Faculty of Medicine, University of Bonn, Bonn, Germany
| | - Andrea Baccarelli
- Laboratory of Environmental Precision Health, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Murielle Bochud
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Hermann Brenner
- German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
- Network Aging Research, Heidelberg University, Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan Bressler
- Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, 77030, TX, USA
| | - Monique M B Breteler
- Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany
| | - Cristian Carmeli
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
- Population Health Laboratory, University of Fribourg, Fribourg, Switzerland
| | - Layal Chaker
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Tanguy Corre
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center, Jackson, 39216, MS, USA
| | - Simon R Cox
- Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK
| | - Graciela E Delgado
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Arif B Ekici
- Institute of Human Genetics, Friedrich-Alexander-UniversitätErlangen-Nürnberg, 91054, Erlangen, Germany
| | - Karlhans Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - James S Floyd
- Department of Medicine, University of Washington, Seattle, 98101, WA, USA
- Department of Epidemiology, University of Washington, Seattle, 98101, WA, USA
- Cardiovascular Health Research Unit, University of Washington, Seattle, 98101, WA, USA
| | - Eliza Fraszczyk
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Xu Gao
- Laboratory of Environmental Precision Health, Mailman School of Public Health, Columbia University, New York, NY, USA
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, China
| | - Xīn Gào
- German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
| | - Allan C Gelber
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Sahar Ghasemi
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Christian Gieger
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
| | - Philip Greenland
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Megan L Grove
- Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, 77030, TX, USA
| | - Sarah E Harris
- Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK
| | - Gibran Hemani
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Peter Henneman
- Department of Clinical Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, the Netherlands
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA
- Biostatistics, Fielding School of Public Health, UCLA, Los Angeles, CA, USA
| | - Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Mikko A Hurme
- Department of Microbiology and Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland
| | - Shih-Jen Hwang
- Framingham Heart Study, Framingham, MA, USA
- Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sharon L R Kardia
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Silva Kasela
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Marcus E Kleber
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany
| | - Wolfgang Koenig
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance, Munich, Germany
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Jaspal S Kooner
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK
- Imperial College Healthcare NHS Trust, London, UK
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Brigitte Kühnel
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
| | - Christine Ladd-Acosta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Centre, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Dan Liu
- Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Donald M Lloyd-Jones
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Stefan Lorkowski
- Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena, Germany
| | - Ake T Lu
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA
| | - Riccardo E Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Winfried März
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena, Germany
- Synlab Academy, SYNLAB Holding Deutschland GmbH, Mannheim and Augsburg, Germany
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Daniel L McCartney
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Karlijn A C Meeks
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, the Netherlands
| | - Lili Milani
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Pashupati P Mishra
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Centre, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
| | - Matthias Nauck
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Christoph Nowak
- Department of Neurobiology, Care Sciences and Society (NVS), Family Medicine and Primary Care Unit, Karolinska Institutet, Huddinge, Sweden
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- Ludwig-Maximilians Universität München, Munich, Germany
| | - Holger Prokisch
- Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- Department of Computational Health, Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
| | - Bruce M Psaty
- Department of Medicine, University of Washington, Seattle, 98101, WA, USA
- Department of Epidemiology, University of Washington, Seattle, 98101, WA, USA
- Cardiovascular Health Research Unit, University of Washington, Seattle, 98101, WA, USA
- Department of Health Services, University of Washington, Seattle, 98101, WA, USA
| | - Olli T Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Scott M Ratliff
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Alex P Reiner
- Department of Epidemiology, University of Washington, Seattle, 98101, WA, USA
| | - Ben Schöttker
- German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
- Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Joel Schwartz
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Sanaz Sedaghat
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - Jennifer A Smith
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, 48109, MI, USA
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, University of Washington, Seattle, 98101, WA, USA
| | - Hannah R Stocker
- German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
- Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Silvia Stringhini
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Johan Sundström
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
| | - Brenton R Swenson
- Cardiovascular Health Research Unit, University of Washington, Seattle, 98101, WA, USA
- Institute for Public Health Genetics, University of Washington, Seattle, WA, USA
| | - Joyce B J van Meurs
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Jana V van Vliet-Ostaptchouk
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Andrea Venema
- Department of Clinical Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, the Netherlands
| | - Uwe Völker
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Juliane Winkelmann
- Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
- Chair Neurogenetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Bruce H R Wolffenbuttel
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Yinan Zheng
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Marie Loh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Melanie Waldenberger
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Bavaria, Germany
- DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance, Munich, Germany
| | - Daniel Levy
- Framingham Heart Study, Framingham, MA, USA
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shreeram Akilesh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Owen M Woodward
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Katalin Susztak
- Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, PA, USA
| | - Alexander Teumer
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| | - Anna Köttgen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
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Chen X, Zhao Y, Gao Y, Qi Y, Du J. Outcomes in hepatocellular carcinoma patients undergoing sorafenib treatment: toxicities, cellular oxidative stress, treatment adherence, and quality of life: Erratum. Anticancer Drugs 2021; 32:345-364. [PMID: 33417326 DOI: 10.1097/cad.0000000000001029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou
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19
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Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11:76-98. [PMID: 33274014 PMCID: PMC7672939 DOI: 10.4331/wjbc.v11.i3.76] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/22/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.
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Affiliation(s)
- Tiannan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Jing Wang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Xinge Hu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Xian-Ju Huang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
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20
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Holman GD. Structure, function and regulation of mammalian glucose transporters of the SLC2 family. Pflugers Arch 2020; 472:1155-1175. [PMID: 32591905 PMCID: PMC7462842 DOI: 10.1007/s00424-020-02411-3] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 12/12/2022]
Abstract
The SLC2 genes code for a family of GLUT proteins that are part of the major facilitator superfamily (MFS) of membrane transporters. Crystal structures have recently revealed how the unique protein fold of these proteins enables the catalysis of transport. The proteins have 12 transmembrane spans built from a replicated trimer substructure. This enables 4 trimer substructures to move relative to each other, and thereby alternately opening and closing a cleft to either the internal or the external side of the membrane. The physiological substrate for the GLUTs is usually a hexose but substrates for GLUTs can include urate, dehydro-ascorbate and myo-inositol. The GLUT proteins have varied physiological functions that are related to their principal substrates, the cell type in which the GLUTs are expressed and the extent to which the proteins are associated with subcellular compartments. Some of the GLUT proteins translocate between subcellular compartments and this facilitates the control of their function over long- and short-time scales. The control of GLUT function is necessary for a regulated supply of metabolites (mainly glucose) to tissues. Pathophysiological abnormalities in GLUT proteins are responsible for, or associated with, clinical problems including type 2 diabetes and cancer and a range of tissue disorders, related to tissue-specific GLUT protein profiles. The availability of GLUT crystal structures has facilitated the search for inhibitors and substrates and that are specific for each GLUT and that can be used therapeutically. Recent studies are starting to unravel the drug targetable properties of each of the GLUT proteins.
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Affiliation(s)
- Geoffrey D Holman
- Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK.
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21
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Chen M, Ye C, Zhu J, Zhang P, Jiang Y, Lu X, Wu H. Bergenin as a Novel Urate-Lowering Therapeutic Strategy for Hyperuricemia. Front Cell Dev Biol 2020; 8:703. [PMID: 32850823 PMCID: PMC7403512 DOI: 10.3389/fcell.2020.00703] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/10/2020] [Indexed: 12/11/2022] Open
Abstract
Bergenin is a C-glucoside of 4-O-methyl gallic acid isolated from several medicinal plants and has multiple biological activities. The aim of this study was to assess the potential usefulness of bergenin in hyperuricemia. We found that bergenin reduced serum urate levels in hyperuricemia mice by promoting renal and gut uric acid excretion. Bergenin treatment increased Abcg2 expression both in the kidneys and intestine, while the expression of Slc2a9 was suppressed in the kidney and increased in the intestine. Moreover, bergenin induced ABCG2 expression in HK-2 and Caco-2 cells, as well as SLC2A9 in Caco-2 cells, via the activation of PPARγ. Nevertheless, bergenin suppressed SLC2A9 expression in HK-2 cells by inhibiting the nuclear translocation of p53. Furthermore, bergenin decreased the serum levels of IL-6, IL-1β, and TNF-α in hyperuricemia mice, and promoted a polarization shift from the M1 to M2 phenotype in RAW264.7 cells. In conclusion, these findings provide evidence supporting the further development of bergenin as a novel therapeutic strategy for hyperuricemia.
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Affiliation(s)
- Mo Chen
- Department of Rheumatology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chenyi Ye
- Department of Orthopedic, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianing Zhu
- Department of Rheumatology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Peiyu Zhang
- Department of Rheumatology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yujie Jiang
- Department of Rheumatology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyong Lu
- Department of Rheumatology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huaxiang Wu
- Department of Rheumatology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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22
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Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch 2020; 472:1273-1298. [PMID: 32591906 PMCID: PMC7462924 DOI: 10.1007/s00424-020-02417-x] [Citation(s) in RCA: 276] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 12/13/2022]
Abstract
A family of facilitative glucose transporters (GLUTs) is involved in regulating tissue-specific glucose uptake and metabolism in the liver, skeletal muscle, and adipose tissue to ensure homeostatic control of blood glucose levels. Reduced glucose transport activity results in aberrant use of energy substrates and is associated with insulin resistance and type 2 diabetes. It is well established that GLUT2, the main regulator of hepatic hexose flux, and GLUT4, the workhorse in insulin- and contraction-stimulated glucose uptake in skeletal muscle, are critical contributors in the control of whole-body glycemia. However, the molecular mechanism how insulin controls glucose transport across membranes and its relation to impaired glycemic control in type 2 diabetes remains not sufficiently understood. An array of circulating metabolites and hormone-like molecules and potential supplementary glucose transporters play roles in fine-tuning glucose flux between the different organs in response to an altered energy demand.
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23
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Heterogeneity of Glucose Transport in Lung Cancer. Biomolecules 2020; 10:biom10060868. [PMID: 32517099 PMCID: PMC7356687 DOI: 10.3390/biom10060868] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
Increased glucose uptake is a known hallmark of cancer. Cancer cells need glucose for energy production via glycolysis and the tricarboxylic acid cycle, and also to fuel the pentose phosphate pathway, the serine biosynthetic pathway, lipogenesis, and the hexosamine pathway. For this reason, glucose transport inhibition is an emerging new treatment for different malignancies, including lung cancer. However, studies both in animal models and in humans have shown high levels of heterogeneity in the utilization of glucose and other metabolites in cancer, unveiling a complexity that is difficult to target therapeutically. Here, we present an overview of different levels of heterogeneity in glucose uptake and utilization in lung cancer, with diagnostic and therapeutic implications.
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24
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Lu YH, Chang YP, Li T, Han F, Li CJ, Li XY, Xue M, Cheng Y, Meng ZY, Han Z, Sun B, Chen LM. Empagliflozin Attenuates Hyperuricemia by Upregulation of ABCG2 via AMPK/AKT/CREB Signaling Pathway in Type 2 Diabetic Mice. Int J Biol Sci 2020; 16:529-542. [PMID: 32015688 PMCID: PMC6990905 DOI: 10.7150/ijbs.33007] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 09/20/2019] [Indexed: 12/16/2022] Open
Abstract
Hyperuricemia (HUA) is a metabolic disease characterized by elevated serum uric acid (SUA). Empagliflozin, a kind of sodium-glucose cotransporter 2 inhibitors, has recently emerged as a new antidiabetic agent by facilitating glucose excretion in urine. Moreover, there was evidence of SUA reduction following treatment with empagliflozin in addition to glycaemic control, while the molecular mechanisms remain unknown. To investigate the potential mechanisms, the model of type 2 diabetes (T2DM) with HUA was established by combination of peritoneal injection of potassium oxonate and intragastric administration of hypoxanthine in KK-Ay mice. A series of method such as RT-PCR, western blot, immunochemistry, immunofluorescence were conducted to explore the mechanism. Our results showed that empagliflozin significantly ameliorated the levels of SUA and blood glucose in T2DM mice with HUA. Furthermore, in both kidney and ileum, empagliflozin obviously promoted protein expression of uric acid (UA) transporter ABCG2, p-AMPK, p-AKT and p-CREB. The same trend was observed in human tubular epithelial (HK-2) cells. Additionally, through application of an AMPK inhibitor (Compound C), it was further confirmed empagliflozin exerted its anti-hyperuricemic effects in an AMPK dependent manner. Meanwhile, with the help of ChIP assay and luciferase reporter gene assay, we found that CREB further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Taken together, our study demonstrated that empagliflozin treatment played an essential role in attenuating HUA by upregulation of ABCG2 via AMPK/AKT/CREB signaling pathway.
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Affiliation(s)
- Yun-Hong Lu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China.,Tianjin Medical University General Hospital Airport Hospital, Tianjin 300308
| | - Yun-Peng Chang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China.,Department of Endocrinology and Metabolism, the Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin 300170, China
| | - Ting Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Fei Han
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Chun-Jun Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Xiao-Yu Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Mei Xue
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Ying Cheng
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Zi-Yu Meng
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Zhe Han
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Li-Ming Chen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
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25
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Han X, Yang J, Li D, Guo Z. Overexpression of Uric Acid Transporter SLC2A9 Inhibits Proliferation of Hepatocellular Carcinoma Cells. Oncol Res 2019. [PMID: 29523220 PMCID: PMC7848443 DOI: 10.3727/096504018x15199489058224] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Although the mechanisms of HCC progression are not well understood, recent studies demonstrated the potential contribution of uric acid transporter SLC2A9 to tumor suppression. However, the roles and underlying mechanisms are still unknown. We aimed to study the roles and mechanisms of SLC2A9 in HCC. The present study showed that SLC2A9 expression was decreased in human HCC tissues and cell lines. In addition, overexpression of SLC2A9 inhibited HCC cell proliferation. SCL2A9 induced HCC cell apoptosis by inhibiting the expression of caspase 3. Our study also revealed that upregulation of SLC2A9 reduced intracellular reactive oxygen species (ROS) accumulation. Furthermore, SLC2A9 increased the mRNA and protein expression of tumor suppressor p53 in HCC cells. Probenecid inhibits SLC2A9-mediated uric acid transport, which promotes cell proliferation, inhibits cell apoptosis, induces intracellular ROS, and decreases the expression of p53 in HCC cells. Therefore, the present study demonstrated that SLC2A9 may be a novel tumor suppressor gene and a potential therapeutic target in HCC.
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Affiliation(s)
- Xiaoying Han
- Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, P.R. China
| | - Jing Yang
- Department of Oncology, Xuzhou City Hospital of Traditional Chinese Medicine, Xuzhou, P.R. China
| | - Dong Li
- Department of Oncology, Xuzhou Central Hospital, Xuzhou, Jiangsu, P.R. China
| | - Zewei Guo
- Department of Internal Medicine, Huangshan Traditional Chinese Medicine, Huangshan, Anhui, P.R. China
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26
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Mehmood A, Zhao L, Wang C, Hossen I, Raka RN, Zhang H. Stevia residue extract increases intestinal uric acid excretion via interactions with intestinal urate transporters in hyperuricemic mice. Food Funct 2019; 10:7900-7912. [DOI: 10.1039/c9fo02032b] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The supplementation of STVRE significantly attenuated hyperuricemia and oxidative stress, upregulated ABCG2 and downregulated GLUT9 (protein and mRNA) expression in hyperuricemic mice.
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Affiliation(s)
- Arshad Mehmood
- Beijing Advance Innovation Center for Food Nutrition and Human Health
- Beijing Technology and Business University
- Beijing 100048
- China
- Beijing Engineering and Technology Research Center of Food Additives
| | - Lei Zhao
- Beijing Advance Innovation Center for Food Nutrition and Human Health
- Beijing Technology and Business University
- Beijing 100048
- China
- Beijing Engineering and Technology Research Center of Food Additives
| | - Chengtao Wang
- Beijing Advance Innovation Center for Food Nutrition and Human Health
- Beijing Technology and Business University
- Beijing 100048
- China
- Beijing Engineering and Technology Research Center of Food Additives
| | - Imam Hossen
- Beijing Advance Innovation Center for Food Nutrition and Human Health
- Beijing Technology and Business University
- Beijing 100048
- China
- Beijing Engineering and Technology Research Center of Food Additives
| | - Rifat Nowshin Raka
- Beijing Advance Innovation Center for Food Nutrition and Human Health
- Beijing Technology and Business University
- Beijing 100048
- China
- Beijing Engineering and Technology Research Center of Food Additives
| | - Huimin Zhang
- Beijing Advance Innovation Center for Food Nutrition and Human Health
- Beijing Technology and Business University
- Beijing 100048
- China
- Beijing Engineering and Technology Research Center of Food Additives
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27
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Effects of Chicory on Serum Uric Acid, Renal Function, and GLUT9 Expression in Hyperuricaemic Rats with Renal Injury and In Vitro Verification with Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:1764212. [PMID: 30622589 PMCID: PMC6304617 DOI: 10.1155/2018/1764212] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/14/2018] [Accepted: 11/22/2018] [Indexed: 01/08/2023]
Abstract
Hyperuricaemia (HUA) is an independent risk factor for chronic kidney disease. Urate crystals are deposited in the kidney and can cause renal tubular interstitial fibrosis, leading to renal dysfunction. Chicory extract (hereafter referred to as chicory) clearly reduced serum uric acid levels in rats with HUA induced by 10% fructose. This is the first study to observe the effect of chicory on serum uric acid levels and renal function in rats with HUA and renal injury. In vivo studies using hyperuricaemic rats with renal injury induced by yeast and adenine demonstrated that chicory decreased serum uric acid level, and its effect of delaying the progression of kidney injury was better than that of benzbromarone. In vitro cell experiments showed that this effect is related to the inhibition of GLUT9 protein expression in renal tubules and that lowering blood uric acid concentrations is one of the factors that alleviates renal damage. The results of this study indicate that chicory can be used as an alternative for alleviating renal dysfunction in hyperuricaemia.
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Carreño D, Corro N, Torres-Estay V, Véliz LP, Jaimovich R, Cisternas P, San Francisco IF, Sotomayor PC, Tanasova M, Inestrosa NC, Godoy AS. Fructose and prostate cancer: toward an integrated view of cancer cell metabolism. Prostate Cancer Prostatic Dis 2018; 22:49-58. [PMID: 30104655 DOI: 10.1038/s41391-018-0072-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/13/2018] [Accepted: 06/29/2018] [Indexed: 01/07/2023]
Abstract
Activation of glucose transporter-1 (Glut-1) gene expression is a molecular feature of cancer cells that increases glucose uptake and metabolism. Increased glucose uptake is the basis for the clinical localization of primary tumors using positron emission tomography (PET) and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) as a radiotracer. However, previous studies have demonstrated that a considerable number of cancers, which include prostate cancer (CaP), express low to undetectable levels of Glut-1 and that FDG-PET has limited clinical applicability in CaP. This observation could be explained by a low metabolic activity of CaP cells that may be overcome using different hexoses, such as fructose, as the preferred energy source. However, these hypotheses have not been examined critically in CaP. This review article summarizes what is currently known about transport and metabolism of hexoses, and more specifically fructose, in CaP and provides experimental evidences indicating that CaP cells may have increased capacity to transport and metabolize fructose in vitro and in vivo. Moreover, this review highlights recent findings that allow better understanding of how metabolism of fructose may regulate cancer cell proliferation and how fructose uptake and metabolism, through the de novo lipogenesis pathway, may provide new opportunities for CaP early diagnosis, staging, and treatment.
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Affiliation(s)
- Daniela Carreño
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Néstor Corro
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Loreto P Véliz
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Pedro Cisternas
- Centro de Envejecimiento y Regeneración (CARE), Department of Cell Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Paula C Sotomayor
- Center for Integrative Medicine and Innovative Science, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
| | - Marina Tanasova
- Department of Chemistry, Michigan Technological University, Houghton, MI, 49931, USA
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE), Department of Cell Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro S Godoy
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile. .,Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
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29
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Auberson M, Stadelmann S, Stoudmann C, Seuwen K, Koesters R, Thorens B, Bonny O. SLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney. Pflugers Arch 2018; 470:1739-1751. [PMID: 30105595 PMCID: PMC6224025 DOI: 10.1007/s00424-018-2190-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 07/17/2018] [Accepted: 08/01/2018] [Indexed: 02/07/2023]
Abstract
Uric acid (UA) is a metabolite of purine degradation and is involved in gout flairs and kidney stones formation. GLUT9 (SLC2A9) was previously shown to be a urate transporter in vitro. In vivo, humans carrying GLUT9 loss-of-function mutations have familial renal hypouricemia type 2, a condition characterized by hypouricemia, UA renal wasting associated with kidney stones, and an increased propensity to acute renal failure during strenuous exercise. Mice carrying a deletion of GLUT9 in the whole body are hyperuricemic and display a severe nephropathy due to intratubular uric acid precipitation. However, the precise role of GLUT9 in the kidney remains poorly characterized. We developed a mouse model in which GLUT9 was deleted specifically along the whole nephron in a tetracycline-inducible manner (subsequently called kidney-inducible KO or kiKO). The urate/creatinine ratio was increased as early as 4 days after induction of the KO and no GLUT9 protein was visible on kidney extracts. kiKO mice are morphologically identical to their wild-type littermates and had no spontaneous kidney stones. Twenty-four-hour urine collection revealed a major increase of urate urinary excretion rate and of the fractional excretion of urate, with no difference in urate concentration in the plasma. Polyuria was observed, but kiKO mice were still able to concentrate urine after water restriction. KiKO mice displayed lower blood pressure accompanied by an increased heart rate. Overall, these results indicate that GLUT9 is a crucial player in renal handling of urate in vivo and a putative target for uricosuric drugs.
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Affiliation(s)
- Muriel Auberson
- Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1011, Lausanne, Switzerland
| | - Sophie Stadelmann
- Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1011, Lausanne, Switzerland
| | - Candice Stoudmann
- Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1011, Lausanne, Switzerland
| | - Klaus Seuwen
- Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland
| | | | - Bernard Thorens
- Centre for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Olivier Bonny
- Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1011, Lausanne, Switzerland. .,Service of Nephrology, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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30
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Abstract
Xenopus laevis oocytes are a useful heterologous expression system for expressing glucose transporters (GLUTs) and examining their functions. In this chapter, we provide a detailed protocol on oocyte extraction and preparation for GLUT9 protein expression. Furthermore, we describe the determination of GLUT9 overexpression level by biotinylation and Western blotting analysis. Finally, we also describe how GLUT9-expressing oocytes can be used to measure urate kinetics by radioisotopes as well as two-microelectrode voltage clamping techniques.
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31
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Placental Expression of Glucose Transporter Proteins in Pregnancies Complicated by Gestational and Pregestational Diabetes Mellitus. Can J Diabetes 2018; 42:209-217. [DOI: 10.1016/j.jcjd.2017.04.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 04/18/2017] [Accepted: 04/24/2017] [Indexed: 12/31/2022]
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32
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Szablewski L. Distribution of glucose transporters in renal diseases. J Biomed Sci 2017; 24:64. [PMID: 28854935 PMCID: PMC5577680 DOI: 10.1186/s12929-017-0371-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 08/23/2017] [Indexed: 02/06/2023] Open
Abstract
Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney.Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three families of glucose transporters: GLUT proteins, sodium-dependent glucose transporters (SGLTs) and SWEET. In kidney, only GLUTs and SGLTs protein are expressed. Mutations within genes that code these proteins lead to different renal disorders and diseases. However, diseases, not only renal, such as diabetes, may damage expression and function of renal glucose transporters.
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Affiliation(s)
- Leszek Szablewski
- Medical University of Warsaw, Chair & Department of General Biology & Parasitology, Center for Biostructure Research, 5 Chalubinskiego Str., 02-004, Warsaw, Poland.
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33
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Kobylecki CJ, Afzal S, Nordestgaard BG. Plasma Urate, Cancer Incidence, and All-Cause Mortality: A Mendelian Randomization Study. Clin Chem 2017; 63:1151-1160. [PMID: 28428355 DOI: 10.1373/clinchem.2016.268185] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 02/14/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Observationally, high plasma urate is associated with high risk of cancer. We used a Mendelian randomization design to test the hypothesis that high concentrations of plasma urate are associated with high cancer incidence and all-cause mortality observationally and genetically. METHODS We performed observational and genetic analyses using plasma urate and the urate solute carrier family 2 member 9 (SLC2A9) rs7442295 genotype in 86210 individuals from the Copenhagen General Population Study. Cancer and mortality end points were from national cancer and death registries. Incidences and risk of cancer and all-cause mortality were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. RESULTS During a median follow-up time of 3.9 years for cancer and 4.9 years for all-cause mortality, 3243 individuals received a diagnosis of cancer and 3978 died. Observationally, 50% higher plasma urate was associated with multivariable-adjusted hazard ratios of 1.11 (95% CI, 1.05-1.18) for cancer incidence and 1.07 (1.01-1.13) for all-cause mortality. Each A-allele of the SLC2A9 rs7442295 was associated with 9% higher plasma urate and hazard ratios of 1.07 (1.01-1.14) for cancer incidence and 1.07 (1.02-1.13) for all-cause mortality. In instrumental variable analyses, the odds ratios for a genetically determined 50% higher plasma urate was 1.22 (1.02-1.47) for cancer incidence and 1.49 (1.13-1.93) for all-cause mortality. CONCLUSIONS High plasma urate was both observationally and genetically associated with high cancer incidence and high all-cause mortality, suggesting causal relationships.
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Affiliation(s)
- Camilla J Kobylecki
- Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Shoaib Afzal
- Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; .,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
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34
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Bu P, Le Y, Zhang Y, Cheng X. Hormonal and Chemical Regulation of the Glut9 Transporter in Mice. J Pharmacol Exp Ther 2017; 360:206-214. [PMID: 27807007 DOI: 10.1124/jpet.116.237040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 10/27/2016] [Indexed: 03/08/2025] Open
Abstract
Glucose transporter (Glut) 9 plays an important role in maintaining the homeostasis of uric acid in the body. Although the physiologic functions of Glut9 have been well established, the regulation of Glut9 expression is less well understood. In this study, we showed that the mRNA and protein expression of Glut9 in mouse liver and kidney are female predominant. Ontogeny studies further revealed that the female-predominant Glut9 expression in mouse liver only occurs in adult mice, which is primarily attributable to the fact that Glut9 expression sustains in females but gradually decreases in males after it reaches the peak level at day 22. Hormone replacement studies in gonadectomized mice, lit/lit mice, and hypophysectomized mice demonstrated that female-predominant Glut9 expression in mouse liver and kidney are primarily due to the inhibitory effects of male-pattern growth hormone secretion, but not sex hormones. In silico analysis of DNA sequences revealed that conserved response elements of signal transducer and activator of transcription 5b, which is an established relay molecule in the growth hormone signaling pathway, are present in mouse and human Glut9/GLUT9 gene promoters, suggesting that Glut9/GLUT9 is a potential target gene of growth hormone. Analysis of mice treated with a panel of chemicals revealed that agonists of the aryl hydrocarbon receptor and the peroxisome proliferator-activated receptor α induced Glut9 mRNA expression in the liver, which is further supported by the presence of conserved xenobiotic response elements and direct repeat 1 DNA motifs in the mouse Glut9 gene promoter. In summary, Glut9 expression is downregulated by male-pattern growth hormone secretion but is upregulated by activation of aryl hydrocarbon receptor and peroxisome proliferator-activated receptor α signaling in mice.
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Affiliation(s)
- Pengli Bu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences (P.B., Y.L., Y.Z., X.C.), and Department of Biological Sciences, College of Liberal Arts and Sciences (P.B.), St. John's University, Queens, New York
| | - Yuan Le
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences (P.B., Y.L., Y.Z., X.C.), and Department of Biological Sciences, College of Liberal Arts and Sciences (P.B.), St. John's University, Queens, New York
| | - Yue Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences (P.B., Y.L., Y.Z., X.C.), and Department of Biological Sciences, College of Liberal Arts and Sciences (P.B.), St. John's University, Queens, New York
| | - Xingguo Cheng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences (P.B., Y.L., Y.Z., X.C.), and Department of Biological Sciences, College of Liberal Arts and Sciences (P.B.), St. John's University, Queens, New York
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35
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Specific regions of the brain are capable of fructose metabolism. Brain Res 2016; 1657:312-322. [PMID: 28034722 DOI: 10.1016/j.brainres.2016.12.022] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 12/21/2022]
Abstract
High fructose consumption in the Western diet correlates with disease states such as obesity and metabolic syndrome complications, including type II diabetes, chronic kidney disease, and non-alcoholic fatty acid liver disease. Liver and kidneys are responsible for metabolism of 40-60% of ingested fructose, while the physiological fate of the remaining fructose remains poorly understood. The primary metabolic pathway for fructose includes the fructose-transporting solute-like carrier transport proteins 2a (SLC2a or GLUT), including GLUT5 and GLUT9, ketohexokinase (KHK), and aldolase. Bioinformatic analysis of gene expression encoding these proteins (glut5, glut9, khk, and aldoC, respectively) identifies other organs capable of this fructose metabolism. This analysis predicts brain, lymphoreticular tissue, placenta, and reproductive tissues as possible additional organs for fructose metabolism. While expression of these genes is highest in liver, the brain is predicted to have expression levels of these genes similar to kidney. RNA in situ hybridization of coronal slices of adult mouse brains validate the in silico expression of glut5, glut9, khk, and aldoC, and show expression across many regions of the brain, with the most notable expression in the cerebellum, hippocampus, cortex, and olfactory bulb. Dissected samples of these brain regions show KHK and aldolase enzyme activity 5-10 times the concentration of that in liver. Furthermore, rates of fructose oxidation in these brain regions are 15-150 times that of liver slices, confirming the bioinformatics prediction and in situ hybridization data. This suggests that previously unappreciated regions across the brain can use fructose, in addition to glucose, for energy production.
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Xu X, Li C, Zhou P, Jiang T. Uric acid transporters hiding in the intestine. PHARMACEUTICAL BIOLOGY 2016; 54:3151-3155. [PMID: 27563755 DOI: 10.1080/13880209.2016.1195847] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 04/19/2016] [Accepted: 05/24/2016] [Indexed: 06/06/2023]
Abstract
CONTEXT Hyperuricaemia is known as an abnormally increased uric acid level in the blood. Although it was observed many years ago, since uric acid excretion via the intestine pathway accounted for approximately one-third of total elimination of uric acid, the molecular mechanism of 'extra-renal excretion' was poorly understood until the finding of uric acid transporters. OBJECTIVE The objective of this study was to gather all information related to uric acid transporters in the intestine and present this information as a comprehensive and systematic review article. METHODS A literature search was performed from various databases (e.g., Medline, Science Direct, Springer Link, etc.). The key terms included uric acid, transporter and intestine. The period for the search is from the 1950s to the present. The bibliographies of papers relating to the review subject were also searched for further relevant references. RESULTS The uric acid transporters identified in the intestine are discussed in this review. The solute carrier (SLC) transporters include GLUT9, MCT9, NPT4, NPT homolog (NPT5) and OAT10. The ATP binding cassette (ABC) transporters include ABCG2 (BCRP), MRP2 and MRP4. Bacterial transporter YgfU is a low-affinity and high-capacity transporter for uric acid. CONCLUSION The present review may be helpful for further our understanding of hyperuricaemia and be of value in designing future studies on novel therapeutic pathways.
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Affiliation(s)
- Xianxiang Xu
- a School of Biomedical Sciences, Huaqiao University , Quanzhou , China
- b Institute of Chinese Meteria Medica, China Academy of Chinese Medical Sciences , Beijing , China
| | - Canghai Li
- b Institute of Chinese Meteria Medica, China Academy of Chinese Medical Sciences , Beijing , China
| | - Pan Zhou
- a School of Biomedical Sciences, Huaqiao University , Quanzhou , China
| | - Tingliang Jiang
- b Institute of Chinese Meteria Medica, China Academy of Chinese Medical Sciences , Beijing , China
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37
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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 2016; 48:1396-1406. [PMID: 27723756 DOI: 10.1038/ng.3695] [Citation(s) in RCA: 461] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 09/15/2016] [Indexed: 02/07/2023]
Abstract
Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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Abstract
The objective of this study is to confirm the precise glucose transporter (GLUT) 8 localization and determine the expression of GLUT9a and GLUT9b by Western blot and confocal and immunoelectron microscopy in the mouse testis and sperm. GLUT8, GLUT9a, and GLUT9b proteins are expressed in the most intraseminiferous tubula cells and Leydig cells. GLUT8 localizes in the midpiece and principal piece as well as in the acrosomal region of the sperm. Immunoelectron microscopic analysis shows that GLUT8 is strongly detectable at the acrosome and neck region of the sperm. In the midpiece, GLUT8 localizes at the outer dense fibers (odf) as well as at the circumference of the spiral mitochondria. In the principal piece, GLUT8 localizes at the odf. GLUT9a strictly localizes in the midpiece, but GLUT9b localizes in the acrosome, midpiece, and principal piece of the sperm. These results suggest that glucose uptake via GLUT8, GLUT9a, and GLUT9b likely affects normal spermatogenesis, steroidogenesis, and sperm function in the mouse.
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Affiliation(s)
- Sung Tae Kim
- Department of Obstetrics and Gynecology,Washington University in St Louis, St Louis, Missouri 63110, USA
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Das Gupta E, Sakthiswary R, Lee SL, Wong SF, Hussein H, Gun SC. Clinical significance of SLC2A9/GLUT9
rs11722228 polymorphisms in gout. Int J Rheum Dis 2016; 21:705-709. [DOI: 10.1111/1756-185x.12918] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Esha Das Gupta
- Department of Medicine; International Medical University; Seremban Malaysia
| | - Rajalingham Sakthiswary
- Department of Medicine; Universiti Kebangsaan Malaysia Medical Centre; Kuala Lumpur Malaysia
| | - Shing L. Lee
- Department of Medicine; International Medical University; Seremban Malaysia
| | - Shew F. Wong
- Department of Medicine; International Medical University; Seremban Malaysia
| | - Heselynn Hussein
- Department of Medicine; Putrajaya Hospital; Wilayah Persekutuan Putrajaya Malaysia
| | - Suk C. Gun
- Department of Medicine; Tuanku Jaafar Hospital; Seremban Malaysia
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Franssens L, Lesuisse J, Wang Y, Willems E, Willemsen H, Koppenol A, Guo X, Buyse J, Decuypere E, Everaert N. The effect of insulin on plasma glucose concentrations, expression of hepatic glucose transporters and key gluconeogenic enzymes during the perinatal period in broiler chickens. Gen Comp Endocrinol 2016; 232:67-75. [PMID: 26723190 DOI: 10.1016/j.ygcen.2015.12.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 12/18/2015] [Accepted: 12/22/2015] [Indexed: 12/27/2022]
Abstract
Chickens have blood glucose concentrations that are twofold higher than those observed in mammals. Moreover, the insulin sensitivity seems to decrease with postnatal age in both broiler and layer chickens. However, little is known about the response of insulin on plasma glucose concentrations and mRNA abundance of hepatic glucose transporters 1, 2, 3, 8, 9 and 12 (GLUT1, 2, 3, 8, 9 and 12) and three regulatory enzymes of the gluconeogenesis, phosphoenolpyruvate carboxykinase 1 and 2 (PCK1 and 2) or fructose-1,6-biphosphatase 1 (FBP1) in chicks during the perinatal period. In the present study, broiler embryos on embryonic day (ED)16, ED18 or newly-hatched broiler chicks were injected intravenously with bovine insulin (1μg/g body weight (BW)) to examine plasma glucose response and changes in hepatic mRNA abundance of the GLUTs, PCK1 and 2 and FBP1. Results were compared with a non-treated control group and a saline-injected sham group. Plasma glucose levels of insulin-treated ED18 embryos recovered faster from their minimum level than those of insulin-treated ED16 embryos or newly-hatched chicks. In addition, at the minimum plasma glucose level seven hours post-injection (PI), hepatic GLUT2, FBP1 and PCK2 mRNA abundance was decreased in insulin-injected embryos, compared to sham and control groups, being most pronounced when insulin injection occurred on ED16.
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Affiliation(s)
- Lies Franssens
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium
| | - Jens Lesuisse
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium
| | - Yufeng Wang
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium
| | - Els Willems
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium
| | - Hilke Willemsen
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium
| | - Astrid Koppenol
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium; ILVO Animal Sciences Unit, Scheldeweg 68, 9090 Melle, Belgium
| | - Xiaoquan Guo
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045 Jiangxi, China
| | - Johan Buyse
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium.
| | - Eddy Decuypere
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium
| | - Nadia Everaert
- KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30, Box 2456, 3001 Leuven, Belgium; University of Liège, Gembloux Agro-Bio Tech, Animal Science Unit, Passage des Déportés 2, 5030 Gembloux, Belgium
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Kovach CP, Al Koborssy D, Huang Z, Chelette BM, Fadool JM, Fadool DA. Mitochondrial Ultrastructure and Glucose Signaling Pathways Attributed to the Kv1.3 Ion Channel. Front Physiol 2016; 7:178. [PMID: 27242550 PMCID: PMC4871887 DOI: 10.3389/fphys.2016.00178] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 05/04/2016] [Indexed: 12/20/2022] Open
Abstract
Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3−∕−) results in “Super-smeller” mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3−∕− mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3−∕− male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3−∕− mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3−∕− mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB.
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Affiliation(s)
- Christopher P Kovach
- Program in Neuroscience, Florida State UniversityTallahassee, FL, USA; Department of Biological Science, Florida State UniversityTallahassee, FL, USA
| | - Dolly Al Koborssy
- Program in Neuroscience, Florida State University Tallahassee, FL, USA
| | - Zhenbo Huang
- Program in Neuroscience, Florida State University Tallahassee, FL, USA
| | | | - James M Fadool
- Program in Neuroscience, Florida State UniversityTallahassee, FL, USA; Department of Biological Science, Florida State UniversityTallahassee, FL, USA
| | - Debra A Fadool
- Program in Neuroscience, Florida State UniversityTallahassee, FL, USA; Department of Biological Science, Florida State UniversityTallahassee, FL, USA; Institute of Molecular Biophysics, Florida State UniversityTallahassee, FL, USA
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Hepatocyte nuclear factor 1 coordinates multiple processes in a model of intestinal epithelial cell function. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1859:591-8. [PMID: 26855178 DOI: 10.1016/j.bbagrm.2016.02.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 02/01/2016] [Accepted: 02/04/2016] [Indexed: 12/26/2022]
Abstract
Mutations in hepatocyte nuclear factor 1 transcription factors (HNF1α/β) are associated with diabetes. These factors are well studied in the liver, pancreas and kidney, where they direct tissue-specific gene regulation. However, they also have an important role in the biology of many other tissues, including the intestine. We investigated the transcriptional network governed by HNF1 in an intestinal epithelial cell line (Caco2). We used chromatin immunoprecipitation followed by direct sequencing (ChIP-seq) to identify HNF1 binding sites genome-wide. Direct targets of HNF1 were validated using conventional ChIP assays and confirmed by siRNA-mediated depletion of HNF1, followed by RT-qPCR. Gene ontology process enrichment analysis of the HNF1 targets identified multiple processes with a role in intestinal epithelial cell function, including properties of the cell membrane, cellular response to hormones, and regulation of biosynthetic processes. Approximately 50% of HNF1 binding sites were also occupied by other members of the intestinal transcriptional network, including hepatocyte nuclear factor 4A (HNF4A), caudal type homeobox 2 (CDX2), and forkhead box A2 (FOXA2). Depletion of HNF1 in Caco2 cells increases FOXA2 abundance and decreases levels of CDX2, illustrating the coordinated activities of the network. These data suggest that HNF1 plays an important role in regulating intestinal epithelial cell function, both directly and through interactions with other intestinal transcription factors.
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Stringer DM, Zahradka P, Taylor CG. Glucose transporters: cellular links to hyperglycemia in insulin resistance and diabetes. Nutr Rev 2016; 73:140-54. [PMID: 26024537 DOI: 10.1093/nutrit/nuu012] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Abnormal expression and/or function of mammalian hexose transporters contribute to the hallmark hyperglycemia of diabetes. Due to different roles in glucose handling, various organ systems possess specific transporters that may be affected during the diabetic state. Diabetes has been associated with higher rates of intestinal glucose transport, paralleled by increased expression of both active and facilitative transporters and a shift in the location of transporters within the enterocyte, events that occur independent of intestinal hyperplasia and hyperglycemia. Peripheral tissues also exhibit deregulated glucose transport in the diabetic state, most notably defective translocation of transporters to the plasma membrane and reduced capacity to clear glucose from the bloodstream. Expression of renal active and facilitative glucose transporters increases as a result of diabetes, leading to elevated rates of glucose reabsorption. However, this may be a natural response designed to combat elevated blood glucose concentrations and not necessarily a direct effect of insulin deficiency. Functional foods and nutraceuticals, by modulation of glucose transporter activity, represent a potential dietary tool to aid in the management of hyperglycemia and diabetes.
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Affiliation(s)
- Danielle M Stringer
- D.M. Stringer was with the Department of Human Nutritional Sciences, University of Manitoba, and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada at the time of manuscript preparation. C.G. Taylor is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. P. Zahradka is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada.
| | - Peter Zahradka
- D.M. Stringer was with the Department of Human Nutritional Sciences, University of Manitoba, and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada at the time of manuscript preparation. C.G. Taylor is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. P. Zahradka is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
| | - Carla G Taylor
- D.M. Stringer was with the Department of Human Nutritional Sciences, University of Manitoba, and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada at the time of manuscript preparation. C.G. Taylor is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. P. Zahradka is with the Department of Human Nutritional Sciences, University of Manitoba; the Department of Physiology, University of Manitoba; and the Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
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Mancikova A, Krylov V, Hurba O, Sebesta I, Nakamura M, Ichida K, Stiburkova B. Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin Exp Nephrol 2015; 20:578-584. [DOI: 10.1007/s10157-015-1186-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 10/13/2015] [Indexed: 11/28/2022]
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Long W, Panwar P, Witkowska K, Wong K, O'Neill D, Chen XZ, Lemieux MJ, Cheeseman CI. Critical Roles of Two Hydrophobic Residues within Human Glucose Transporter 9 (hSLC2A9) in Substrate Selectivity and Urate Transport. J Biol Chem 2015; 290:15292-303. [PMID: 25922070 DOI: 10.1074/jbc.m114.611178] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Indexed: 12/22/2022] Open
Abstract
High blood urate levels (hyperuricemia) have been found to be a significant risk factor for cardiovascular diseases and inflammatory arthritis, such as hypertension and gout. Human glucose transporter 9 (hSLC2A9) is an essential protein that mainly regulates urate/hexose homeostasis in human kidney and liver. hSLC2A9 is a high affinity-low capacity hexose transporter and a high capacity urate transporter. Our previous studies identified a single hydrophobic residue in trans-membrane domain 7 of class II glucose transporters as a determinant of fructose transport. A mutation of isoleucine 335 to valine (I355V) in hSLC2A9 can reduce fructose transport while not affecting glucose fluxes. This current study demonstrates that the I335V mutant transports urate similarly to the wild type hSLC2A9; however, Ile-335 is necessary for urate/fructose trans-acceleration exchange to occur. Furthermore, Trp-110 is a critical site for urate transport. Two structural models of the class II glucose transporters, hSLC2A9 and hSLC2A5, based on the crystal structure of hSLC2A1 (GLUT1), reveal that Ile-335 (or the homologous Ile-296 in hSLC2A5) is a key component for protein conformational changes when the protein translocates substrates. The hSLC2A9 model also predicted that Trp-110 is a crucial site that could directly interact with urate during transport. Together, these studies confirm that hSLC2A9 transports both urate and fructose, but it interacts with them in different ways. Therefore, this study advances our understanding of how hSLC2A9 mediates urate and fructose transport, providing further information for developing pharmacological agents to treat hyperuricemia and related diseases, such as gout, hypertension, and diabetes.
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Affiliation(s)
| | - Pankaj Panwar
- the Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada and
| | - Kate Witkowska
- the Department of Clinical Pharmacology, John Vane Science Centre, William Harvey Research Centre, Charter House Square Campus, QMUL, London EC16BQ, England
| | | | | | | | - M Joanne Lemieux
- the Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada and
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Affiliation(s)
- Asim K. Mandal
- Renal Divisions, Brigham and Women's Hospital and VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115;
| | - David B. Mount
- Renal Divisions, Brigham and Women's Hospital and VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115;
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Simon KC, Eberly S, Gao X, Oakes D, Tanner CM, Shoulson I, Fahn S, Schwarzschild MA, Ascherio A. Mendelian randomization of serum urate and parkinson disease progression. Ann Neurol 2014; 76:862-8. [PMID: 25257975 DOI: 10.1002/ana.24281] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 09/22/2014] [Accepted: 09/23/2014] [Indexed: 01/24/2023]
Abstract
OBJECTIVE Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach. METHODS The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment. RESULTS Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. INTERPRETATION This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.
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Affiliation(s)
- Kelly Claire Simon
- Department of Nutrition, Harvard School of Public Health, Boston, MA; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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Prestin K, Wolf S, Feldtmann R, Hussner J, Geissler I, Rimmbach C, Kroemer HK, Zimmermann U, Meyer zu Schwabedissen HE. Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α. Am J Physiol Renal Physiol 2014; 307:F1041-51. [PMID: 25209865 DOI: 10.1152/ajprenal.00640.2013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Renal tubular handling of urate is realized by a network of uptake and efflux transporters, including members of drug transporter families such as solute carrier proteins and ATP-binding cassette transporters. Solute carrier family 2, member 9 (SLC2A9), is one key factor of this so called "urate transportosome." The aim of the present study was to understand the transcriptional regulation of SLC2A9 and to test whether identified factors might contribute to a coordinated transcriptional regulation of the transporters involved in urate handling. In silico analysis and cell-based reporter gene assays identified a hepatocyte nuclear factor (HNF)4α-binding site in the promoter of SLC2A9 isoform 1, whose activity was enhanced by transient HNF4α overexpression, whereas mutation of the binding site diminished activation. HNF4α overexpression induced endogenous SLC2A9 expression in vitro. The in vivo role of HNF4α in the modulation of renal SLC2A9 gene expression was supported by findings of quantitative real-time RT-PCR analyses and chromatin immunoprecipitation assays. Indeed, mRNA expression of SLC2A9 and HNF4α in human kidney samples was significantly correlated. We also showed that in renal clear cell carcinoma, downregulation of HNF4α mRNA and protein expression was associated with a significant decline in expression of the transporter. Taken together, our data suggest that nuclear receptor family member HNF4α contributes to the transcriptional regulation of SLC2A9 isoform 1. Since HNF4α has previously been assumed to be a modulator of several urate transporters, our findings support the notion that there could be a transcriptional network providing synchronized regulation of the functional network of the urate transportosome.
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Affiliation(s)
- Katharina Prestin
- University of Basel, Department of Pharmaceutical Sciences, Biopharmacy, Basel, Switzerland
| | - Stephanie Wolf
- University Medicine, Ernst Moritz Arndt University Greifswald, Center of Drug Absorption and Transport, Institute of Pharmacology, Greifswald, Germany
| | - Rico Feldtmann
- University Medicine, Ernst Moritz Arndt University Greifswald, Center of Drug Absorption and Transport, Institute of Pharmacology, Greifswald, Germany
| | - Janine Hussner
- University of Basel, Department of Pharmaceutical Sciences, Biopharmacy, Basel, Switzerland
| | - Ingrid Geissler
- University Medicine, Ernst Moritz Arndt University Greifswald, Center of Drug Absorption and Transport, Institute of Pharmacology, Greifswald, Germany
| | - Christian Rimmbach
- University Medicine, Ernst Moritz Arndt University Greifswald, Center of Drug Absorption and Transport, Institute of Pharmacology, Greifswald, Germany
| | - Heyo K Kroemer
- University of Goettingen, Medical Faculty, Goettingen, Germany; and
| | - Uwe Zimmermann
- University Medicine, Ernst Moritz Arndt University Greifswald, Department of Urology, Greifswald, Germany
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Qian Y, Wang X, Chen X. Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics. World J Transl Med 2014; 3:37-57. [DOI: 10.5528/wjtm.v3.i2.37] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 03/25/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Metabolic reprogramming and altered energetics have become an emerging hallmark of cancer and an active area of basic, translational, and clinical cancer research in the recent decade. Development of effective anticancer therapeutics may depend on improved understanding of the altered cancer metabolism compared to that of normal cells. Changes in glucose transport and glycolysis, which are drastically upregulated in most cancers and termed the Warburg effect, are one of major focuses of this new research area. By taking advantage of the new knowledge and understanding of cancer’s mechanisms, numerous therapeutic agents have been developed to target proteins and enzymes involved in glucose transport and metabolism, with promising results in cancer cells, animal tumor models and even clinical trials. It has also been hypothesized that targeting a pathway or a process, such as glucose transport or glucose metabolism, rather than a specific protein or enzyme in a signaling pathway may be more effective. This is based on the observation that cancer somehow can always bypass the inhibition of a target drug by switching to a redundant or compensatory pathway. In addition, cancer cells have higher dependence on glucose. This review will provide background information on glucose transport and metabolism in cancer, and summarize new therapeutic developments in basic and translational research in these areas, with a focus on glucose transporter inhibitors and glycolysis inhibitors. The daunting challenges facing both basic and clinical researchers of the field are also presented and discussed.
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The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense. Oncogene 2014; 34:1799-810. [DOI: 10.1038/onc.2014.119] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 03/04/2014] [Accepted: 03/13/2014] [Indexed: 12/11/2022]
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