Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130021, China.
J Hepatol. 2011 Dec;55(6):1281-90. doi: 10.1016/j.jhep.2011.03.017. Epub 2011 Apr 14.
BACKGROUND & AIMS: Cytosolic phospholipase A(2)α (cPLA(2)α) is a rate-limiting key enzyme controlling the release of arachidonic acid (AA) substrate for the synthesis of prostaglandins and leukotrienes. This study was designed to explore the role of hepatocyte cPLA(2)α in Fas-mediated liver injury, in vivo.
Transgenic mice with targeted expression of cPLA(2)α under control of the albumin-promoter enhancer and wild-type mice were injected intraperitoneally with anti-Fas antibody Jo2 or lipopolysaccharide plus d-galactosamine and monitored for liver injury and survival at various time points.
The cPLA(2)α Tg mice resist Fas-induced liver failure, as reflected by the lower serum transaminase levels, fewer apoptotic hepatocytes, reduced caspase activation, and reduced PARP cleavage when compared to the matched wild type mice. Inhibition of cPLA(2)α by its pharmacological inhibitor, pyrrolidine, enhanced Jo2-induced liver injury in both cPLA(2)α Tg and wild type mice. Hepatic overexpression of cPLA(2)α increases the expression of EGFR in the liver and the EGFR inhibitor, AG1478, exacerbated Jo2-mediated liver injury. The cPLA(2)α transgenic mice develop more prominent liver tissue damage than wild-type mice after LPS/d-galactosamine injection.
Hepatocyte cPLA(2)α protects against Fas-induced liver injury and this effect is mediated at least in part through the upregulation of EGFR.
细胞质型磷脂酶 A2α（cPLA2α）是控制花生四烯酸（AA）释放的限速关键酶，AA 是合成前列腺素和白三烯的底物。本研究旨在探讨肝细胞 cPLA2α 在 Fas 介导的肝损伤中的作用，采用体内实验方法。
在白蛋白启动子增强子的控制下，用靶向表达 cPLA2α 的转基因小鼠和野生型小鼠经腹腔注射抗 Fas 抗体 Jo2 或脂多糖加半乳糖胺，并在不同时间点监测肝损伤和存活情况。
与匹配的野生型小鼠相比，cPLA2αTg 小鼠抵抗 Fas 诱导的肝衰竭，表现为血清转氨酶水平较低、凋亡肝细胞较少、半胱天冬酶激活减少和 PARP 裂解减少。用其药理学抑制剂吡咯烷抑制 cPLA2α 增强了 Jo2 在 cPLA2αTg 和野生型小鼠中的肝损伤。肝过表达 cPLA2α 增加了肝内 EGFR 的表达，EGFR 抑制剂 AG1478 加剧了 Jo2 介导的肝损伤。LPS/半乳糖胺注射后，cPLA2α 转基因小鼠比野生型小鼠发生更明显的肝组织损伤。
肝细胞 cPLA2α 可防止 Fas 诱导的肝损伤，这种作用至少部分是通过上调 EGFR 介导的。
