title: The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism.
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-associated 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 primates, 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 promoter 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.
  
  
  
  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).
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care, Friedrich Schiller University, and Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: von Loeffelholz
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III, University Hospital Dresden, TU Dresden, Germany.|Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lieske
authors.affiliation: Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Neuschäfer-Rube
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III, University Hospital Dresden, TU Dresden, Germany.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Willmes
authors.affiliation: General, Visceral, and Transplantation Surgery, Charité-University School of Medicine, Berlin, Germany.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Raschzok
authors.affiliation: General, Visceral, and Transplantation Surgery, Charité-University School of Medicine, Berlin, Germany.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Sauer
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care, Friedrich Schiller University, and Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Horn
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Dresden, TU Dresden, Germany.
authors.forename: Antonios
authors.initials: A
authors.lastname: Chatzigeorgiou
authors.affiliation: Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pathe-Neuschäfer-Rube
authors.affiliation: Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Charité-University School of Medicine, Berlin, Germany.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Andreas F H
authors.initials: AFH
authors.lastname: Pfeiffer
authors.affiliation: Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.|Department of Internal Medicine, Catholic University of Rome, Rome, Italy.
authors.forename: Geltrude
authors.initials: G
authors.lastname: Mingrone
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III, University Hospital Dresden, TU Dresden, Germany.|German Center for Diabetes Research, Neuherberg, Germany.|Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Max Planck Institute for Metabolism Research, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Stroehle
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research, Charité-University School of Medicine, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.affiliation: Max Planck Institute for Metabolism Research, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Helfand
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD.
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Dresden, TU Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, Germany.
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Püschel
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III, University Hospital Dresden, TU Dresden, Germany.|German Center for Diabetes Research, Neuherberg, Germany.|Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.|Study Center for Metabolic Vascular Medicine, GWT-TU Dresden, Germany.|Paul Langerhans Institute Dresden of the Helmholtz Center Munich at, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D002478:Cells, Cultured; D000072017:Deubiquitinating Enzymes / Q000235:genetics*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D050356:Lipid Metabolism / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D012494:Sampling Studies
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D000072017:Deubiquitinating Enzymes; C000622060:MINDY1 protein, human