PuSH - Publication Server of Helmholtz Zentrum München: The human longevity gene homolog <em>INDY</em> and interleukin-6 interact in hepatic lipid metabolism.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

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)

Publ. Version/Full Text

DOI

PMC

	Free by publisher

Open Access Green as soon as Postprint is submitted to ZB.

Abstract
Metrics
Extra information

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.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

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

Publisher Wiley

Publishing Place Hoboken, NJ

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Pancreatic Beta Cell Research (IPI)