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/ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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