e., TNF-α, MCP-1, and IL-18). In addition, adipose tissue from
these mice had up-regulated expression of adiponectin, PPARγ, and IRS-1 in parallel with reduced JNK phosphorylation, suggesting an insulin-sensitizing effect of the lack of 5-LO in this tissue. Furthermore, hepatocytes isolated from ApoE−/− mice lacking 5-LO were more resistant to damage. Interestingly, 5-LO products (i.e., LTB4, LTD4, and 5-HETE) made hepatocytes more susceptible to TNF-α–induced apoptosis through mechanisms related to the suppression of NF-κB activity. To our knowledge, this is the first study reporting the impact of 5-LO products on hepatocyte survival and the implication of 5-LO in the progression of hepatic inflammation in metabolic liver disease. The initial stages of NAFLD are characterized by simple steatosis or fatty liver with no detectable inflammation followed Maraviroc solubility dmso by the combination of steatosis with inflammation, which is known as steatohepatitis.1, 2 The findings obtained in our study with ApoE−/− mice clearly dissociate steatosis and inflammation in
the liver. Indeed, compared with ApoE−/− mice, we found that ApoE−/−/5-LO−/− mice showed reduced hepatic inflammation but a comparable degree of hepatic steatosis, suggesting see more that hepatic inflammation can develop independently of steatosis. Consistent with this finding, striking changes were observed in the expression of inflammatory genes in the livers of ApoE−/−/5-LO−/− mice. Among these genes, we detected a reduction in MCP-1, which is a potent chemoattractant protein that contributes to the maintenance of the inflammatory infiltrate during liver injury, and its expression has been shown to be elevated in patients with chronic viral hepatitis and in experimental models of liver injury.30, 31 We also detected learn more a significant reduction in TNF-α, considered one of the main cytokines involved
in hepatocellular damage,32 and in IL-18, which causes liver injury by induction of Fas-dependent hepatocyte apoptosis.33 Together, our findings indicate that 5-LO is an important factor in the transition from steatosis to steatohepatitis. Our data also provide evidence that 5-LO regulates adipose tissue biology in ApoE−/− mice. Indeed, the absence of 5-LO in these mice was associated with an increased expression of adiponectin in parallel with a decrease in MCP-1 and IL-6 in adipose tissue. Whereas adiponectin appears to induce beneficial effects in NAFLD by decreasing liver injury and attenuating fibrogenesis,34, 35 MCP-1 and IL-6 are two regulatory adipokines that work as an interface between metabolism and inflammation.