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The human longevity gene homolog INDY and Interleukin-6 Interact in hepatic Lipid metabolism

von Loeffelholz, C. and Lieske, S. and Neuschäfer-Rube, F. and Willmes, D. and Raschzok, N. and Sauer, I. and König, J. and Fromm, M. and Horn, P. and Chatzigeorgiou, A. and Pathe-Neuschäfer-Rube, A. and Jordan, J. and Pfeiffer, A. and Mingrone, G. and Bornstein, S. and Stroehle, P. and Harms, C. and Wunderlich, F. and Helfand, S. and Bernier, M. and de Cabo, R. and Shulman, G. and Chavakis, T. and Püschel, G. and Birkenfeld, A. (2017) The human longevity gene homolog INDY and Interleukin-6 Interact in hepatic Lipid metabolism. Hepatology (66), pp. 616-630. DOI: 10.1002/hep.29089 ISSN 0270-9139

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Abstract

Reduced expression of the Indy (“I am Not Dead, Yet”) gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane–associ- ated citrate transporter expressed highly in the liver, protects mice from high-fat diet–induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman pri- mates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy pro- moter was determined. Activation of the IL-6–signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. Conclusion: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (HEPATOLOGY 2017;66:616-630).

Item URL in elib:https://elib.dlr.de/118766/
Document Type:Article
Title:The human longevity gene homolog INDY and Interleukin-6 Interact in hepatic Lipid metabolism
Authors:
AuthorsInstitution or Email of AuthorsAuthors ORCID iD
von Loeffelholz, C.Friedrich Schiller University, Jena, GermanyUNSPECIFIED
Lieske, S.University Hospital Dresden, Dresden, GermanyUNSPECIFIED
Neuschäfer-Rube, F.Universität Potsdam, Potsdam, GermanyUNSPECIFIED
Willmes, D.University Hospital Dresden, Dresden, GermanyUNSPECIFIED
Raschzok, N.Charité-University School of Medicine, Berlin, GermanyUNSPECIFIED
Sauer, I.Charité-University School of Medicine, Berlin, GermanyUNSPECIFIED
König, J.Friedrich-Alexander-University, Erlangen-Nürnberg, GermanyUNSPECIFIED
Fromm, M.Friedrich-Alexander-University, Erlangen-Nürnberg, GermanyUNSPECIFIED
Horn, P.Friedrich Schiller University, Jena, GermanyUNSPECIFIED
Chatzigeorgiou, A.University Clinic Dresden, Dresden, GermanyUNSPECIFIED
Pathe-Neuschäfer-Rube, A.Universität Potsdam, Potsdam, GermanyUNSPECIFIED
Jordan, J.Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Pfeiffer, A.Charité-University School of Medicine, Berlin, GermanyUNSPECIFIED
Mingrone, G.King's College London, London, UKUNSPECIFIED
Bornstein, S.University Hospital Dresden, Desden, GermanyUNSPECIFIED
Stroehle, P.Max Planck Institute for Metabolism Research, Cologne, GermanyUNSPECIFIED
Harms, C.Charité-University School of Medicine, Berlin, GermanyUNSPECIFIED
Wunderlich, F.Max Planck Institute for Metabolism Research, Cologne, GermanyUNSPECIFIED
Helfand, S.Brown University, Providence, RIUNSPECIFIED
Bernier, M.Brown University, Providence, RIUNSPECIFIED
de Cabo, R.Brown University, Providence, RIUNSPECIFIED
Shulman, G.Yale University School of Medicine, Hew Haven, CTUNSPECIFIED
Chavakis, T.University Clinic Dresden, Dresden, GermanyUNSPECIFIED
Püschel, G.Universität Potsdam, Potsdam, GermanyUNSPECIFIED
Birkenfeld, A.University Hospital Dresden, Dresden, GermanyUNSPECIFIED
Date:2017
Journal or Publication Title:Hepatology
Refereed publication:Yes
Open Access:No
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
DOI :10.1002/hep.29089
Page Range:pp. 616-630
ISSN:0270-9139
Status:Published
Keywords:Human Longevity, INDY, Interleukin-6
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 - Forschung unter Weltraumbedingungen
DLR - Research theme (Project):R - Projekt :envihab
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Leitungsbereich ME
Deposited By: Jackman, Sabine
Deposited On:06 Feb 2018 11:47
Last Modified:06 Feb 2018 11:47

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