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

Fang, Chongye, Cai, Xianbin, Hayashi, Shuhei, Hao, Shumei, Sakiyama, Haruhiko, Wang, Xuanjun, Yang, Qin, Akira, Shizuo, Nishiguchi, Shuhei, Fujiwara, Noriko, Tsutsui, Hiroko, Sheng, Jun
Biochimica et biophysica acta 2019 v.1864 no.3 pp. 271-280
adipocytes, caffeine, fatty liver, hepatocytes, hepatoprotective effect, interleukin-6, knockout mutants, liver, macrophages, messenger RNA, mice, muscles, myotubes, oxygen consumption, risk reduction
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.