TY - JOUR
T1 - The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism
AU - von Loeffelholz, Christian
AU - Lieske, Stefanie
AU - Neuschäfer-Rube, Frank
AU - Willmes, Diana M.
AU - Raschzok, Nathanael
AU - Sauer, Igor M.
AU - König, Jörg
AU - Fromm, Martin F.
AU - Horn, Paul
AU - Chatzigeorgiou, Antonios
AU - Pathe-Neuschäfer-Rube, Andrea
AU - Jordan, Jens
AU - Pfeiffer, Andreas F.H.
AU - Mingrone, Geltrude
AU - Bornstein, Stefan R.
AU - Stroehle, Peter
AU - Harms, Christoph
AU - Wunderlich, F. Thomas
AU - Helfand, Stephen L.
AU - Bernier, Michel
AU - de Cabo, Rafael
AU - Shulman, Gerald I.
AU - Chavakis, Triantafyllos
AU - Püschel, Gerhard P.
AU - Birkenfeld, Andreas L.
PY - 2017/7/19
Y1 - 2017/7/19
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014417037&partnerID=8YFLogxK
U2 - 10.1002/hep.29089
DO - 10.1002/hep.29089
M3 - Article
AN - SCOPUS:85014417037
SN - 0270-9139
VL - 66
SP - 616
EP - 630
JO - Hepatology
JF - Hepatology
IS - 2
ER -
