7C). This study collectively shows, for the first time, the implication of 12/15-LO

in the pathogenesis of liver injury in an experimental model of NAFLD secondary to hyperlipidemia. Our findings demonstrate that the Dinaciclib chemical structure genetic disruption of Alox15 protects hyperlipidemia-prone ApoE−/− mice against hepatic steatosis, inflammation, and cell injury. The ApoE-deficient mouse spontaneously develops typical hepatic lesions on a chow diet that faithfully mimics human NAFLD progression from simple hepatic triglyceride accumulation (steatosis) to a combination of steatosis with a marked inflammatory component and cell injury (steatohepatitis).6, 7 The accumulation of triglycerides in the cytosol of hepatocytes in ApoE−/− mice appears to be the consequence of the regulation exerted by the ApoE protein on the very low-density lipoprotein assembly–secretion cascade.27, 28 On the other hand, the inflammatory liver phenotype displayed by ApoE−/− mice is characterized by increased oxidative stress, necroinflammation and macrophage infiltration, and increased susceptibility to exacerbated fibrosis.6, 7 The hepatoprotection exerted by the disruption of Alox15 in ApoE−/− mice was characterized by the presence of lower serum ALT levels, a sensitive selleckchem marker

of liver injury, as well as by the reduction in the number of hepatic inflammatory foci and the immunostaining for F4/80, indicative of decreased macrophage infiltration. In parallel with these biochemical and histological findings, we detected significant reductions in the expression of TNFα, considered one of the main cytokines involved in hepatocyte injury,29 and IL-18, which causes liver injury through induction of Fas-dependent hepatocyte apoptosis.30 Moreover, mice lacking Alox15 showed a striking reduction in the expression of MCP-1, which is a potent chemoattractant

protein that Ribonucleotide reductase contributes to the maintenance of the inflammatory infiltrate during liver injury and the expression of which is elevated in patients and animal models of liver disease.31, 32 This finding is consistent with the existence of a direct link between the 12/15-LO pathway and the expression of MCP-1 in macrophages.33 Importantly, disruption of Alox15 in ApoE−/− mice was associated with a remarkable protection from hepatocyte apoptosis, as revealed by caspase-3 immunostaining. This protective effect was corroborated in vitro in hepatocytes isolated from ApoE−/−/12/15-LO−/− mice, which were more resistant to apoptosis, even following treatment with actinomycin D, which is a potent RNA inhibitor that sensitizes hepatocytes to TNFα-induced cell death.34 These findings are compatible with previous studies showing that pancreatic β cells overexpressing Alox15 display increased rates of cell death.