Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice

Rickenbacher A, Jang JH, Limani P, Ungethum U, Lehmann K, Oberkofler CE, Weber A, Graf R, Humar B, Clavien PA.

J Hepatol 2014; 61: 301-308.

Speaker: Yu-Lun, Chen (陳昱倫)                                         Time: 15:00~16:00, Nov. 19, 2014

Commentator: Dr. Chih-Peng, Chang (張志鵬 老師)         Place: Room 601

Abstract:

       Ischemia reperfusion injury (IRI) is the tissue damage caused by excessive immune response when blood supply returns to the tissue after a period of ischemia which is a major cause of the postoperative complications arising from surgery. (1) Previous studies showed that calorie restriction mitigates ischemic organ injury, (2) but the underlying mechanisms remain unclear. Here, the authors clarified that starvation protects liver against ischemia reperfusion (IR) through either energy-preserving or anti-inflammatory mechanism. The author establishes a hepatic ischemia animal model using C57BL6 mice to investigate how fasting provides against IR injury. The fasting was performed by supply water only. Injury was assessed by investigating AST/ALT level and histology. Raw264-7 macrophage-like cells were investigated in vitro. Their findings showed that fasting for one, but not two or three days, protected the fasted mice from hepatic IR injury by reducing the response of innate immune cells rather than improving ATP supply. Although the number of kupffer cells (KCs, liver resident macrophages) did not change upon fasting, the reduced inflammatory response and neutrophil recruitment observed in the fasted liver confirmed that the activity of KCs was suppressed. Furthermore, the authors found that the decrease of circulating HMGB1 level, a key signal for the activation of KCs following IR, is associated with the up-regulation of autophagy. The authors further revealed that Sirt1, a molecule responsible for starvation and autophagic response, plays a role in mediate circulating HMGB1 reduction. In conclusion, short-time fasting protects the mice from hepatic IR injury via Sirt1-dependent down-regulation of circulating HMGB1. The reduction in serum HMGB1 appears to be mediated by its engagement in the autophagic response.

References:

1.     Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am J Transplant 2011; 11: 1563-1569.

2.     Chandrasekar B, Nelson JF, Colston JT, Freeman GL. Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2001; 280: H2094-H2102.