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Pharmacol Rev. 2020 Jan;72(1):343-379. doi: 10.1124/pr.118.015735.

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease.

Author information

1
Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.).
2
Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.) Andreas.Birkenfeld@med.uni-tuebingen.de.

Abstract

The solute carrier (SLC) superfamily comprises more than 400 transport proteins mediating the influx and efflux of substances such as ions, nucleotides, and sugars across biological membranes. Over 80 SLC transporters have been linked to human diseases, including obesity and type 2 diabetes (T2D). This observation highlights the importance of SLCs for human (patho)physiology. Yet, only a small number of SLC proteins are validated drug targets. The most recent drug class approved for the treatment of T2D targets sodium-glucose cotransporter 2, product of the SLC5A2 gene. There is great interest in identifying other SLC transporters as potential targets for the treatment of metabolic diseases. Finding better treatments will prove essential in future years, given the enormous personal and socioeconomic burden posed by more than 500 million patients with T2D by 2040 worldwide. In this review, we summarize the evidence for SLC transporters as target structures in metabolic disease. To this end, we identified SLC13A5/sodium-coupled citrate transporter, and recent proof-of-concept studies confirm its therapeutic potential in T2D and nonalcoholic fatty liver disease. Further SLC transporters were linked in multiple genome-wide association studies to T2D or related metabolic disorders. In addition to presenting better-characterized potential therapeutic targets, we discuss the likely unnoticed link between other SLC transporters and metabolic disease. Recognition of their potential may promote research on these proteins for future medical management of human metabolic diseases such as obesity, fatty liver disease, and T2D. SIGNIFICANCE STATEMENT: Given the fact that the prevalence of human metabolic diseases such as obesity and type 2 diabetes has dramatically risen, pharmacological intervention will be a key future approach to managing their burden and reducing mortality. In this review, we present the evidence for solute carrier (SLC) genes associated with human metabolic diseases and discuss the potential of SLC transporters as therapeutic target structures.

PMID:
31882442
DOI:
10.1124/pr.118.015735

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