5‐lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor α–induced hepatocyte damage in hyperlipidemia‐prone ApoE‐null mice

The actual risk factors that drive hepatic inflammation during the transition from steatosis to steatohepatitis are unknown. We recently demonstrated that hyperlipidemia‐prone apolipoprotein E–deficient (ApoE−/−) mice exhibit hepatic steatosis and increased susceptibility to hepatic inflammation and advanced fibrosis. Because the proinflammatory 5‐lipoxygenase (5‐LO) pathway was found to be up‐regulated in these mice and given that 5‐LO deficiency confers cardiovascular protection to ApoE−/− mice, we determined the extent to which the absence of 5‐LO would alter liver injury in these mice. Compared with ApoE−/− mice, which showed expected hepatic steatosis and inflammation, ApoE/5‐LO double‐deficient (ApoE−/−/5‐LO−/−) mice exhibited reduced hepatic inflammation, macrophage infiltration, tumor necrosis factor α (TNF‐α), monocyte chemoattractant protein‐1 (MCP‐1) and interleukin (IL)‐18 expression, caspase‐3 and nuclear factor‐κB (NF‐κB) activities, and serum alanine aminotransferase levels in the absence of changes in hepatic steatosis. The lack of 5‐LO produced a remarkable insulin‐sensitizing effect in the adipose tissue because peroxisome proliferator‐activated receptor γ, insulin receptor substrate‐1, and adiponectin were up‐regulated, whereas c‐Jun amino‐terminal kinase phosphorylation and MCP‐1 and IL‐6 expression were down‐regulated. On the other hand, hepatocytes isolated from ApoE−/−/5‐LO−/− mice were more resistant to TNF‐α–induced apoptosis. The 5‐LO products leukotriene (LT) B4, LTD4, and 5‐HETE consistently triggered TNF‐α–induced apoptosis and compromised hepatocyte survival by suppressing NF‐κB activity in the presence of actinomycin D. Moreover, ApoE−/−/5‐LO−/− mice were protected against sustained high‐fat diet (HFD)‐induced liver injury and hepatic inflammation, macrophage infiltration and insulin resistance were significantly milder than those of ApoE−/− mice. Finally, pharmacological inhibition of 5‐LO significantly reduced hepatic inflammatory infiltrate in the HFD and ob/ob models of fatty liver disease. Conclusion: These combined data indicate that hyperlipidemic mice lacking 5‐LO are protected against hepatic inflammatory injury, suggesting that 5‐LO is involved in mounting hepatic inflammation in metabolic disease. (HEPATOLOGY 2010.)