5-Lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor α-induced hepatocyte damage in hyperlipidemia-prone apoe-null mice

Abstract

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 (TNF-), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, caspase-3 and nuclear factor-B (NF-B) 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 , 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--induced apoptosis. The 5-LO products leukotriene (LT) B4, LTD4, and 5-HETE consistently triggered TNF--induced apoptosis and compromised hepatocyte survival by suppressing NF-B 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 in-filtration 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. Copyright © 2010 by the American Association for the Study of Liver Diseases.