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Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)ORCID iD: 0000-0002-9681-5129
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmaceutical Cell Biology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)
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2020 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 8, article id 579Article in journal (Refereed) Published
Abstract [en]

Many newly identified solute carriers (SLCs) and putative transporters have the possibility to be intricately involved in glucose metabolism. Here we show that many transporters of this type display a high degree of regulation at both mRNA and protein level following no or low glucose availability in mouse cortex cultures. We show that this is also the case in Drosophila melanogaster subjected to starvation or diets with different sugar content. Interestingly, re-introduction of glucose to media, or refeeding flies, normalized the gene expression of a number of the targets, indicating a fast and highly dynamic control. Our findings demonstrate high conservation of these transporters and how dependent both cell cultures and organisms are on gene and protein regulation during metabolic fluctuations. Several transporter genes were regulated simultaneously maybe to initiate alternative metabolic pathways as a response to low glucose levels, both in the cell cultures and in D. melanogaster. Our results display that newly identified SLCs of Major Facilitator Superfamily type, as well as the putative transporters included in our study, are regulated by glucose availability and could be involved in several cellular aspects dependent of glucose and/or its metabolites. Recently, a correlation between dysregulation of glucose in the central nervous system and numerous diseases such as obesity, type 2 diabetes mellitus as well as neurological disease such as Alzheimer’s and Parkinson’s diseases indicate a complex regulation and fine tuning of glucose levels in the brain. The fact that almost one third of transporters and transporter-related proteins remain orphans with unknown or contradictive substrate profile, location and function, pinpoint the need for further research about them to fully understand their mechanistic role and their impact on cellular metabolism.

Place, publisher, year, edition, pages
2020. Vol. 8, article id 579
National Category
Cell and Molecular Biology Neurosciences Biochemistry Molecular Biology Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-416363DOI: 10.3389/fcell.2020.00579ISI: 000553395800001PubMedID: 32733888OAI: oai:DiVA.org:uu-416363DiVA, id: diva2:1454498
Funder
Swedish Research Council, 2016-01972The Swedish Brain Foundation, FO2018-0130Swedish Society for Medical Research (SSMF), 201507Novo Nordisk, 34224Stiftelsen Olle Engkvist Byggmästare, 20160614Magnus Bergvall Foundation, 201601754Available from: 2020-07-16 Created: 2020-07-16 Last updated: 2025-02-20Bibliographically approved
In thesis
1. Characterization of Novel Solute Carriers in Humans, Mice and Flies: Solute Carriers in a Broad and Narrow Perspective
Open this publication in new window or tab >>Characterization of Novel Solute Carriers in Humans, Mice and Flies: Solute Carriers in a Broad and Narrow Perspective
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The solute carrier family is the largest family of membrane-bound transporters in humans, with 430 members divided into 65 subfamilies. They transport various substrates across lipid barriers and are vital for absorption, distribution, metabolism and excretion in all cell types in the body. Despite being involved in vital functions, and their effect on both physiology and pathophysiology, many transporters are not characterized. The aim of this thesis was to study newly identified putative solute carriers of which little is known. In Paper I, the relationship of solute carriers in humans and fruit flies was studied. The study revealed that 54 of the 65 subfamilies in humans have one or more orthologues in fruit flies, and a total of 381 orthologues were identified in fruit flies. In Paper II, a comprehensive study of the putative solute carriers and their response to different sugar concentrations were performed. Several, but not all, putative solute carriers were altered in cell cultures maintained in media containing low or no glucose, and the expression normalized upon refeeding with glucose. Similar results were observed in fruit flies subjected to complete starvation or diets with varying sugar concentrations. Last, in Paper III and IV, characterization of one putative solute carrier, UNC93A, was performed. The studies revealed that UNC93A was a conserved protein with an abundant expression in the body of mice but with a restricted expression in fruit flies. The protein was found to possibly be expressed at, or close to, the plasma membrane of cells and to co-localize with Twik-Acid sensitive potassium channels. UNC93A was found to be important for the renal function in fruit flies and to affect survival and membrane potentials in cells. The findings of this thesis establish a high conservation of several putative solute carriers and that they have a highly dynamic regulation during fluctuating energy and glucose availability. Further, while several clear biological aspects of UNC93A was identified, the exact function of transporter proteins is cumbersome to find and more research about these transporters is needed to fully understand their mechanistic role and their association and/or involvement in health and sickness.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 81
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 287
Keywords
Solute carrier, SLC, Putative SLCs, Major facilitator superfamily, MFS, Drosophila melanogaster, Glucose metabolism, UNC93A, CG4928
National Category
Cell Biology Cell and Molecular Biology Evolutionary Biology Biochemistry Molecular Biology Basic Medicine
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-416506 (URN)978-91-513-0980-4 (ISBN)
Public defence
2020-10-16, A1:107a, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2020-09-01 Created: 2020-07-27 Last updated: 2025-02-20Bibliographically approved

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Ceder, Mikaela M.Lekholm, EmiliaKlaesson, AxelTripathi, RekhaSchweizer, NadineFredriksson, Robert

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