Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease

Fatty liver, formerly associated predominantly with excessive alcohol intake, is now also recognized as a complication of obesity and an important precursor state to more severe forms of liver pathology including ischemia/reperfusion injury. No standard protocol for treating fatty liver exists at this time. We therefore examined the effects of 10 days of interleukin 6 (IL‐6) injection in 3 murine models of fatty liver: leptin deficient ob/ob mice, ethanol‐fed mice, and mice fed a high‐fat diet. In all 3 models, IL‐6 injection decreased steatosis and normalized serum aminotransferase. The beneficial effects of IL‐6 treatment in vivo resulted in part from an increase in mitochondrial β oxidation of fatty acid and an increase in hepatic export of triglyceride and cholesterol. However, administration of IL‐6 to isolated cultured steatotic hepatocytes failed to decrease lipid contents, suggesting that the beneficial effects of IL‐6 in vivo do not result from its effects on hepatocytes alone. IL‐6 treatment increased hepatic peroxisome proliferator‐activated receptor (PPAR) α and decreased liver and serum tumor necrosis factor (TNF) α. Finally, 10 days of treatment with IL‐6 prevented the susceptibility of fatty livers to warm ischemia/reperfusion injury. In conclusion, long‐term IL‐6 administration ameliorates fatty livers and protects against warm ischemia/reperfusion fatty liver injury, suggesting the therapeutic potential of IL‐6 in treating human fatty liver disease. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2004;40:933–941.)