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

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 i...

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Autores principales: Zahn, Grit, Willmes, Diana M., El-Agroudy, Nermeen N., Yarnold, Christopher, Jarjes-Pike, Richard, Schaertl, Sabine, Schreiter, Kay, Gehrmann, Wiebke, Wong, Andrea Kuan Cie, Zordan, Tommaso, König, Jörg, Jordan, Jens, Birkenfeld, Andreas L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491/
https://www.ncbi.nlm.nih.gov/pubmed/36005604
http://dx.doi.org/10.3390/metabo12080732
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author Zahn, Grit
Willmes, Diana M.
El-Agroudy, Nermeen N.
Yarnold, Christopher
Jarjes-Pike, Richard
Schaertl, Sabine
Schreiter, Kay
Gehrmann, Wiebke
Wong, Andrea Kuan Cie
Zordan, Tommaso
König, Jörg
Jordan, Jens
Birkenfeld, Andreas L.
author_facet Zahn, Grit
Willmes, Diana M.
El-Agroudy, Nermeen N.
Yarnold, Christopher
Jarjes-Pike, Richard
Schaertl, Sabine
Schreiter, Kay
Gehrmann, Wiebke
Wong, Andrea Kuan Cie
Zordan, Tommaso
König, Jörg
Jordan, Jens
Birkenfeld, Andreas L.
author_sort Zahn, Grit
collection PubMed
description 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.
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spelling pubmed-94134912022-08-27 A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity Zahn, Grit Willmes, Diana M. El-Agroudy, Nermeen N. Yarnold, Christopher Jarjes-Pike, Richard Schaertl, Sabine Schreiter, Kay Gehrmann, Wiebke Wong, Andrea Kuan Cie Zordan, Tommaso König, Jörg Jordan, Jens Birkenfeld, Andreas L. Metabolites Article 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. MDPI 2022-08-08 /pmc/articles/PMC9413491/ /pubmed/36005604 http://dx.doi.org/10.3390/metabo12080732 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zahn, Grit
Willmes, Diana M.
El-Agroudy, Nermeen N.
Yarnold, Christopher
Jarjes-Pike, Richard
Schaertl, Sabine
Schreiter, Kay
Gehrmann, Wiebke
Wong, Andrea Kuan Cie
Zordan, Tommaso
König, Jörg
Jordan, Jens
Birkenfeld, Andreas L.
A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
title A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
title_full A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
title_fullStr A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
title_full_unstemmed A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
title_short A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
title_sort novel and cross-species active mammalian indy (nact) inhibitor ameliorates hepatic steatosis in mice with diet-induced obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413491/
https://www.ncbi.nlm.nih.gov/pubmed/36005604
http://dx.doi.org/10.3390/metabo12080732
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