von Loeffelholz, Christian, Lieske, Stefanie, Neuschaefer-Rube, Frank, Willmes, Diana M., Raschzok, Nathanael ORCID: 0000-0001-5074-7063, Sauer, Igor M., Koenig, Joerg ORCID: 0000-0001-7016-5482, Fromm, Martin F., Horn, Paul ORCID: 0000-0002-8755-7703, Chatzigeorgiou, Antonios ORCID: 0000-0002-7039-4223, Pathe-Neuschaefer-Rube, Andrea, Jordan, Jens, Pfeiffer, Andreas F. H., Mingrone, Geltrude ORCID: 0000-0003-2021-528X, Bornstein, Stefan R., Stroehle, Peter, Harms, Christoph ORCID: 0000-0002-2063-2860, Wunderlich, F. Thomas, Helfand, Stephen L., Bernier, Michel ORCID: 0000-0002-5948-368X, de Cabo, Rafael ORCID: 0000-0002-3354-2442, Shulman, Gerald I. ORCID: 0000-0003-1529-5668, Chavakis, Triantafyllos, Pueschel, Gerhard P. and Birkenfeld, Andreas L. ORCID: 0000-0003-1407-9023 (2017). The Human Longevity Gene Homolog INDY and Interleukin-6 Interact in Hepatic Lipid Metabolism. Hepatology, 66 (2). S. 616 - 631. HOBOKEN: WILEY. ISSN 1527-3350

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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-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. Conclusion: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
von Loeffelholz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lieske, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuschaefer-Rube, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willmes, Diana M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raschzok, NathanaelUNSPECIFIEDorcid.org/0000-0001-5074-7063UNSPECIFIED
Sauer, Igor M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, JoergUNSPECIFIEDorcid.org/0000-0001-7016-5482UNSPECIFIED
Fromm, Martin F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, PaulUNSPECIFIEDorcid.org/0000-0002-8755-7703UNSPECIFIED
Chatzigeorgiou, AntoniosUNSPECIFIEDorcid.org/0000-0002-7039-4223UNSPECIFIED
Pathe-Neuschaefer-Rube, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jordan, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfeiffer, Andreas F. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mingrone, GeltrudeUNSPECIFIEDorcid.org/0000-0003-2021-528XUNSPECIFIED
Bornstein, Stefan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroehle, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harms, ChristophUNSPECIFIEDorcid.org/0000-0002-2063-2860UNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helfand, Stephen L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernier, MichelUNSPECIFIEDorcid.org/0000-0002-5948-368XUNSPECIFIED
de Cabo, RafaelUNSPECIFIEDorcid.org/0000-0002-3354-2442UNSPECIFIED
Shulman, Gerald I.UNSPECIFIEDorcid.org/0000-0003-1529-5668UNSPECIFIED
Chavakis, TriantafyllosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pueschel, Gerhard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Birkenfeld, Andreas L.UNSPECIFIEDorcid.org/0000-0003-1407-9023UNSPECIFIED
URN: urn:nbn:de:hbz:38-223439
DOI: 10.1002/hep.29089
Journal or Publication Title: Hepatology
Volume: 66
Number: 2
Page Range: S. 616 - 631
Date: 2017
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1527-3350
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COUPLED CITRATE TRANSPORTER; FATTY LIVER-DISEASE; SYSTEMIC INSULIN-RESISTANCE; LIFE-SPAN; ADIPOSE-TISSUE; CAENORHABDITIS-ELEGANS; IL-6-DEFICIENT MICE; FUNCTIONAL FEATURES; INDUCED STEATOSIS; SKELETAL-MUSCLEMultiple languages
Gastroenterology & HepatologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22343

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