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

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57 Citations (Scopus)

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 (CCl4) was injected into mice, Pafah2-/- mice showed a delay in hepatic injury recovery. Moreover, after CCl4 administration, liver levels of the esterified form of 8-iso-PGF, 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 and protects tissue from oxidative stress-induced injury.

Original languageEnglish
Pages (from-to)1628-1636
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number3
DOIs
Publication statusPublished - 2008 Jan 18

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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