We have shown that Alox15, the gene encoding for 12/
15-lipoxygenase (12/15-LO), is markedly up-regulated in livers from
apolipoprotein E-deficient (
ApoE(-/-)) mice, which spontaneously develop
nonalcoholic fatty liver disease secondary to
hyperlipidemia. In the current study, we used
ApoE(-/-) mice with a targeted disruption of the Alox15 gene to assess the role of 12/15-LO in the development and progression of hepatic steatosis and
inflammation. Compared with
ApoE(-/-) mice, which exhibited extensive hepatic
lipid accumulation and exacerbated inflammatory injury,
ApoE/12/15-LO double-knockout (
ApoE(-/-)/12/15-LO(-/-)) mice showed reduced serum
alanine aminotransferase levels; decreased hepatic steatosis,
inflammation, and macrophage infiltration; and decreased
fatty acid synthase,
tumor necrosis factor α (TNFα),
monocyte chemoattractant protein-1 (MCP-1),
interleukin (IL)-18, and
IL-6 expression. Remarkably, disruption of Alox15 attenuated
glucose intolerance and high-fat diet-induced
insulin resistance, up-regulated
insulin receptor substrate-2, and exerted opposite effects on hepatic
c-Jun amino-terminal kinase and
adenosine monophosphate-activated
protein kinase phosphorylation, known negative and positive regulators of
insulin signaling, respectively. In adipose tissue, the absence of Alox15 induced significant reductions in the expression of the proinflammatory and
insulin-resistant
adipokines MCP-1, TNFα, and
resistin while increasing the expression of
glucose transporter-4. Interestingly, compared with
ApoE(-/-) mice, which exhibited increased hepatic
caspase-3 staining,
ApoE(-/-)/12/15-LO(-/-) mice showed attenuated hepatocellular injury. Consistent with this finding, hepatocytes isolated from
ApoE(-/-) mice were more vulnerable to TNFα-induced programmed cell death, an effect that was not observed in hepatocytes carrying a targeted disruption of the Alox15 gene.
CONCLUSION: