Caffeine-stimulated muscle IL-6 mediates alleviation of non-alcoholic fatty liver disease

Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circula...

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Published in:Biochimica et biophysica acta. Molecular and cell biology of lipids 2019-03, Vol.1864 (3), p.271-280
Main Authors: Fang, Chongye, Cai, Xianbin, Hayashi, Shuhei, Hao, Shumei, Sakiyama, Haruhiko, Wang, Xuanjun, Yang, Qin, Akira, Shizuo, Nishiguchi, Shuhei, Fujiwara, Noriko, Tsutsui, Hiroko, Sheng, Jun
Format: Article
Language:English
Subjects:
Caffeine
IL-6
NAFLD
Oxygen consumption
Skeletal muscle
STAT3
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Summary:Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circulating IL-6 levels, leading to STAT3 activation in the liver. Interestingly, the expression of IL-6 mRNA was not increased in the liver, but increased substantially in the muscles of caffeine-treated mice. Caffeine was found to stimulate IL-6 production in cultured myotubes but not in hepatocytes, adipocytes, or macrophages. The inhibition of p38/MAPK abrogated caffeine-induced IL-6 production in muscle cells. Caffeine failed to improve NAFLD in IL-6 and hepatocyte-specific STAT3 knockout mice, indicating that the IL-6/STAT3 pathway is vital for the hepatoprotective effects of caffeine in NAFLD. The possibility that IL-6/STAT3-mediated hepatic autophagosome induction and hepatocytic oxygen consumption are involved in the anti-NAFLD effects of caffeine cannot be excluded, based on the findings presented here. Our results reveal that caffeine ameliorates NAFLD via crosstalk between muscle IL-6 production and liver STAT3 activation. [Display omitted] •Caffeine induces IL-6 by skeletal muscle.•Muscle-derived IL-6 activates hepatic STAT3 signaling.•IL-6 promotes autophagy influx and oxygen consumption.•Caffeine ameliorates diet-induced non-alcoholic fatty liver disease.
ISSN:1388-1981
1879-2618
DOI:10.1016/j.bbalip.2018.12.003