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von Loeffelholz, C.* ; Lieske, S. ; Neuschäfer-Rube, F.* ; Willmes, D.M. ; Raschzok, N.* ; Sauer, I.M.* ; König, J.* ; Fromm, M.* ; Horn, P.* ; Chatzigeorgiou, A. ; Pathe-Neuschäfer-Rube, A.* ; Jordan, J.* ; Pfeiffer, A.F.H.* ; Mingrone, G.* ; Bornstein, S.R. ; Ströhle, P.* ; Harms, C.* ; Wunderlich, F.T.* ; Helfand, S.L.* ; Bernier, M.* ; de Cabo, R.* ; Shulman, G.I.* ; Chavakis, T. ; Püschel, G.P.* ; Birkenfeld, A.L.

The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism.

Hepatology 66, 616-630 (2017)
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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 and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In non-human primates, a two 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 via the IL-6-receptor (IL-6R) and activation of the transcription factor Stat3 and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-Stat3 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 non-human primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 via mINDY. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.
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Publication type Article: Journal article
Document type Scientific Article
Keywords IL-6; Indy; Insulin Resistance; Liver; NAFLD; Coupled Citrate Transporter; Fatty Liver-disease; Systemic Insulin-resistance; Life-span; Adipose-tissue; Caenorhabditis-elegans; Il-6-deficient Mice; Functional Features; Induced Steatosis; Skeletal-muscle
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Journal Hepatology
Quellenangaben Volume: 66, Issue: 2, Pages: 616-630 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)