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  -