Background & Aims: Chemical composition of hepatic lipids is an evolving player in steatotic liver ischemia/reperfusion (I/R) injury. Thromboxane A2 (TXA2) is a vasoactive pro-inflammatory lipid mediator derived from arachidonic acid (AA), an omega-6 fatty acid (X-6 FA). Reduced tolerance of the macrosteatotic liver to I/R may be related to increased TXA2 synthesis due to the pre- dominance of X-6 FAs.

Methods: TXA2 levels elicited by I/R in ob/ob and wild type mice were assessed by ELISA. Ob/ob mice were fed X-3 FAs enriched diet to reduce hepatic synthesis of AA and TXA2 or treated with selective TXA2 receptor blocker before I/R.

Results:I/R triggered significantly higher hepatic TXA2 produc- tion in ob/ob than wild type animals. Compared with ob/ob mice on regular diet, X-3 FAs supplementation markedly reduced hepatic AA levels before ischemia and consistently blunted hepa- tic TXA2 synthesis after reperfusion. Sinusoidal perfusion and hepatocellular damage were significantly ameliorated despite downregulation of heme oxygenase-1. Hepatic transcript and protein levels of IL-1b and neutrophil recruitment were signifi- cantly diminished after reperfusion. Moreover, TXA2 receptor blockage conferred similar protection without modification of the histological pattern of steatosis. A stronger protection was achieved in the steatotic compared with lean animals.Conclusions:Enhanced I/R injury in the macrosteatotic liver is explained, at least partially, by TXA2 mediated microcirculatory