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  - 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  -