TY - JOUR A1 - von Loeffelholz, Christian A1 - Lieske, Stefanie A1 - Neuschaefer-Rube, Frank A1 - Willmes, Diana M. A1 - Raschzok, Nathanael A1 - Sauer, Igor M. A1 - König, Jörg A1 - Fromm, Martin F. A1 - Horn, Paul A1 - Chatzigeorgiou, Antonios A1 - Pathe-Neuschaefer-Rube, Andrea A1 - Jordan, Jens A1 - Pfeiffer, Andreas F. H. A1 - Mingrone, Geltrude A1 - Bornstein, Stefan R. A1 - Stroehle, Peter A1 - Harms, Christoph A1 - Wunderlich, F. Thomas A1 - Helfand, Stephen L. A1 - Bernier, Michel A1 - de Cabo, Rafael A1 - Shulman, Gerald I. A1 - Chavakis, Triantafyllos A1 - Püschel, Gerhard Paul A1 - Birkenfeld, Andreas L. T1 - The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism BT - official journal of the American Association for the Study of Liver Diseases JF - Hepatology N2 - 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. Y1 - 2017 U6 - https://doi.org/10.1002/hep.29089 SN - 0270-9139 SN - 1527-3350 VL - 66 IS - 2 SP - 616 EP - 630 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Neuschaefer-Rube, Frank A1 - Schraplau, Anne A1 - Schewe, Bettina A1 - Lieske, Stefanie A1 - Kruetzfeldt, Julia-Mignon A1 - Ringel, Sebastian A1 - Henkela, Janin A1 - Birkenfeld, Andreas L. A1 - Püschel, Gerhard Paul T1 - Arylhydrocarbon receptor-dependent mIndy (SIc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes JF - Toxicology N2 - Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, beta-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). mINDY ablation protects against diet-induced steatosis whereas mINDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the mINDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the mINDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the mINDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the mINDY promoter by benzo[a]pyrene. This study thus identified the mINDY as an AhR target gene. AhR-dependent induction of the mINDY gene might contribute to the development of hepatic steatosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved. KW - SLC13A5 KW - Non-alcoholic fatty liver disease KW - NAFLD Y1 - 2015 U6 - https://doi.org/10.1016/j.tox.2015.08.007 SN - 0300-483X VL - 337 SP - 1 EP - 9 PB - Elsevier CY - Clare ER - TY - JOUR A1 - Neuschaefer-Rube, Frank A1 - Lieske, Stefanie A1 - Kuna, Manuela A1 - Henkel, Janin A1 - Perry, Rachel J. A1 - Erion, Derek M. A1 - Pesta, Dominik A1 - Willmes, Diana M. A1 - Brachs, Sebastian A1 - von Loeffelholz, Christian A1 - Tolkachov, Alexander A1 - Schupp, Michael A1 - Pathe-Neuschaefer-Rube, Andrea A1 - Pfeiffer, Andreas F. H. A1 - Shulman, Gerald I. A1 - Püschel, Gerhard Paul A1 - Birkenfeld, Andreas L. T1 - The mammalian INDY homolog is induced by CREB in a rat model of type 2 diabetes JF - Diabetes : a journal of the American Diabetes Association Y1 - 2014 SN - 0012-1797 SN - 1939-327X VL - 63 IS - 3 SP - 1048 EP - 1057 PB - American Diabetes Association CY - Alexandria ER - TY - JOUR A1 - Wiesner, Stefan A1 - Birkenfeld, Andreas L. A1 - Engeli, Stefan A1 - Haufe, Sven A1 - Brechtel, Lars A1 - Wein, J. A1 - Hermsdorf, Mario A1 - Karnahl, Brita A1 - Berlan, Michel A1 - Lafontan, Max A1 - Sweep, Fred C. G. J. A1 - Luft, Friedrich C. A1 - Jordan, Jens T1 - Neurohumoral and metabolic response to exercise in water N2 - Atrial natriuretic peptide (ANP) stimulates lipid mobilization and lipid oxidation in humans. The mechanism appears to promote lipid mobilization during exercise. We tested the hypothesis that water immersion augments exercise- induced ANP release and that the change in ANP availability is associated with increased lipid mobilization and lipid oxidation. In an open randomized and cross-over fashion we studied 17 men (age 31 +/- 3.6 years; body mass index 24 +/- 1.7 kg/m(2); body fat 17 +/- 6.7%) on no medication. Subjects underwent two incremental exercise tests on a bicycle ergometer. One test was conducted on land and the other test during immersion in water up to the xiphoid process. In a subset (n = 7), we obtained electromyography recordings in the left leg. We monitored gas exchange, blood pressure, and heart rate. In addition, we obtained blood samples towards the end of each exercise step to determine ANP, norepinephrine, epinephrine, lactate, free fatty acids, insulin, and glucose concentrations. Heart rate, systolic blood pressure, and oxygen consumption at the anaerobic threshold and during peak exercise were similar on land and with exercise in water. The respiratory quotient was mildly reduced when subjects exercised in water. Glucose and lactate measurements were decreased whereas free fatty acid concentrations were increased with exercise in water. Water immersion attenuated epinephrine and norepinephrine and augmented ANP release during exercise. Even though water immersion blunts exercise-induced sympathoadrenal activation, lipid mobilization and lipid oxidation rate are maintained or even improved. The response may be explained by augmented ANP release. Y1 - 2010 UR - http://www.thieme-connect.com/ejournals/toc/hmr U6 - https://doi.org/10.1055/s-0030-1248250 SN - 0018-5043 ER -