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A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity

Zahn, G. and Willmes, D. and El-Agroudy, N. and Yarnold, C. and Jarjes-Pike, R. and Schaertl, S. and Schreiter, K. and Gehrmann, W. and Kuan Cie Wong, A. and Zordan, T. and König, J. and Jordan, J. and Birkenfeld, A. (2022) A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12 (8), p. 732. Multidisciplinary Digital Publishing Institute (MDPI). doi: 10.3390/metabo12080732. ISSN 2218-1989.

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Official URL: https://doi.org/10.3390/metabo12080732

Abstract

Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1. Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (-/-) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD.

Item URL in elib:https://elib.dlr.de/190280/
Document Type:Article
Additional Information:This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation
Title:A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iDORCID Put Code
Zahn, G.Eternygen GmbH, Müllerstrasse 178, 13353 Berlin, GermanyUNSPECIFIEDUNSPECIFIED
Willmes, D.Department of Diabetology Endocrinology and Nephrology, Internal Medicine IV, University Hospital Tübingen, Eberhard Karls University Tübingen, 72074 Tübingen, GermanyUNSPECIFIEDUNSPECIFIED
El-Agroudy, N.Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, GermanyUNSPECIFIEDUNSPECIFIED
Yarnold, C.Evotec (UK) Ltd., Oxfordshire OX14 4RZ, UKUNSPECIFIEDUNSPECIFIED
Jarjes-Pike, R.Evotec (UK) Ltd., Oxfordshire OX14 4RZ, UKUNSPECIFIEDUNSPECIFIED
Schaertl, S.Evotec SE, 22419 Hamburg, GermanyUNSPECIFIEDUNSPECIFIED
Schreiter, K.Evotec International GmbH, 37079 Göttingen, GermanyUNSPECIFIEDUNSPECIFIED
Gehrmann, W.Evotec International GmbH, 37079 Göttingen, GermanyUNSPECIFIEDUNSPECIFIED
Kuan Cie Wong, A.Aptuit (Verona) Srl, an Evotec Company, 37135 Verona, ItalyUNSPECIFIEDUNSPECIFIED
Zordan, T.Aptuit (Verona) Srl, an Evotec Company, 37135 Verona, ItalyUNSPECIFIEDUNSPECIFIED
König, J.Friedrich-Alexander-University, Erlangen-Nürnberg, GermanyUNSPECIFIEDUNSPECIFIED
Jordan, J.UNSPECIFIEDhttps://orcid.org/0000-0003-4518-0706UNSPECIFIED
Birkenfeld, A.Department of Diabetology Endocrinology and Nephrology, Internal Medicine IV, University Hospital Tübingen, Eberhard Karls University Tübingen, 72074 Tübingen, GermanyUNSPECIFIEDUNSPECIFIED
Date:8 August 2022
Journal or Publication Title:Metabolites
Refereed publication:Yes
Open Access:Yes
Gold Open Access:Yes
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:12
DOI:10.3390/metabo12080732
Page Range:p. 732
Publisher:Multidisciplinary Digital Publishing Institute (MDPI)
ISSN:2218-1989
Status:Published
Keywords:MAFLD; NAFLD; NASH; NaCT; SLC13A5; citrate transporter; mINDY; metabolic dysfunction
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Muscle Mechanics and Metabolism
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine
Institute of Aerospace Medicine > Leitungsbereich ME
Deposited By: Schrage, Larissa
Deposited On:22 Nov 2022 10:37
Last Modified:22 Nov 2022 10:37

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