Protection against Oxidative Stress-induced Hepatic Injury by Intracellular Type II Platelet-activating Factor Acetylhydrolase by Metabolism of Oxidized Phospholipids in Vivo

Nozomu Kono,Takao Inoue,Yasukazu Yoshida,Hiroyuki Sato,Tomokazu Matsusue,Hiroyuki Itabe,Etsuo Niki,Junken Aoki,Hiroyuki Arai

doi:10.1074/jbc.m708622200

Abstract

Membrane phospholipids are susceptible to oxidation, which is involved in various pathological processes such as inflammation, atherogenesis, neurodegeneration, and aging. One enzyme that may help to remove oxidized phospholipids from cells is intracellular type II platelet-activating factor acetylhydrolase (PAF-AH (II)), which hydrolyzes oxidatively fragmented fatty acyl chains attached to phospholipids. Overexpression of PAF-AH (II) in cells or tissues was previously shown to suppress oxidative stress-induced cell death. In this study we investigated the functions of PAF-AH (II) by generating PAF-AH (II)-deficient (Pafah2(-/-)) mice. PAF-AH (II) was predominantly expressed in epithelial cells such as kidney proximal and distal tubules, intestinal column epithelium, and hepatocytes. Although PAF-AH activity was almost abolished in the liver and kidney of Pafah2(-/-) mice, Pafah2(-/-) mice developed normally and were phenotypically indistinguishable from wild-type mice. However, mouse embryonic fibroblasts derived from Pafah2(-/-) mice were more sensitive to tert-butylhydroperoxide treatment than those derived from wild-type mice. When carbon tetrachloride (CCl(4)) was injected into mice, Pafah2(-/-) mice showed a delay in hepatic injury recovery. Moreover, after CCl(4) administration, liver levels of the esterified form of 8-iso-PGF(2alpha), a known in vitro substrate of PAF-AH (II), were higher in Pafah2(-/-) mice than in wild-type mice. These results indicate that PAF-AH (II) is involved in the metabolism of esterified 8-isoprostaglandin F(2alpha) and protects tissue from oxidative stress-induced injury.

Highlights

Oxidative stress has been implicated in a number of human diseases including atherosclerosis, cancer, neurodegenerative disorders, and aging [1,2,3,4]
We have shown that the Caenorhabditis elegans orthologue of mammalian platelet-activating factor acetylhydrolase (PAF-AH) (II) is expressed in epithelial cells of C. elegans and plays an important role in epithelial morphogenesis [40]
platelet-activating factor (PAF)-AH (II) Is Expressed in Epithelial Tissues—Western blot analysis showed that PAF-AH (II) was expressed essentially in all the tissues, most abundantly in the liver, kidney, intestine, and testis (Fig. 1A)

Summary

Introduction

Oxidative stress has been implicated in a number of human diseases including atherosclerosis, cancer, neurodegenerative disorders, and aging [1,2,3,4]. The hydrolytic activity in liver and kidney of Pafah2Ϫ/Ϫ mice was only half that of wild-type mice, indicating that PAF-AH (II) contributes significantly to the hydrolysis of oxidized phospholipids and that another enzyme(s) is responsible for the remaining activity in these tissues. Consistent with these previous studies, PAF-AH (II) translocated from the cytosol to membranes in MEFs obtained from wild-type mice upon t-BuOOH treatment (Fig. 5B).

Results

Conclusion