ABSTRACT
Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6−/−) mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.
Footnotes
↵* These authors contributed equally as co-first authors
↵‡ These authors contributed equally as co-senior authors
Competing interests
The authors declare no competing or financial interests.
Author contributions
E.B. and F.R.d.F. conceived and designed the experiments. M.V., A.L.G., F.J.P., D.B., A.S., J.S., S.A. and J.D. performed the experiments. M.R.-C., E.B. and F.J.P. analyzed the data. E.B. and F.R.d.F. wrote the paper.
Funding
The present study was financially supported through funding from the Instituto de Salud Carlos III, Red de Trastornos Adictivos UE-FEDER 2012 (RD12/0028); Ministerio de Economía y Competitividad (PI13/02261); Plan Nacional sobre Drogas 049/2009 and 049/2013; Consejería de Economía, Innovación y Ciencia, Junta de Andalucía UE-FEDER (CTS-433); Consejería de Salud y Bienestar Social, Junta Andalucía (TCMR0019, PI0552, PI0228-2013 and PI0823-2012). E.B. is a tenured investigator through the I3SNS Program of the Andalusian “Progreso y Salud” Foundation, Spain. J.S. received a “Miguel Servet” research contract and grant from the National System of Health (Instituto de Salud Carlos III, grant number CP12/03109). The funders were not involved in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Supplementary material
Supplementary material available online at http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.019166/-/DC1
- Received November 17, 2014.
- Accepted April 17, 2015.
- © 2015. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.