Protection against oxidative stress-induced hepatic injury by intracellular type II platelet-activating factor acetylhydrolase by metabolism of oxidized phospholipids in vivo.
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.
Kono
Nozomu
N
Graduate School of Pharmaceutical Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; PRESTO and CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
Inoue
Takao
T
Graduate School of Pharmaceutical Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; PRESTO and CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
Yoshida
Yasukazu
Y
Human Stress Signal Research Center, National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorikawa, Ikeda, Osaka, 563-8577, Japan.
Sato
Hiroyuki
H
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotenba, Shizuoka, 412-8524, Japan.
Matsusue
Tomokazu
T
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotenba, Shizuoka, 412-8524, Japan.
Itabe
Hiroyuki
H
Department of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Niki
Etsuo
E
Human Stress Signal Research Center, National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorikawa, Ikeda, Osaka, 563-8577, Japan.
Aoki
Junken
J
Graduate School of Pharmaceutical Science, Tohoku University, 6-3 Aoba, Aramaki-aza, Aoba-ku, Sendai 980-8578, Japan.
Arai
Hiroyuki
H
Graduate School of Pharmaceutical Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; PRESTO and CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan. Electronic address: harai@mol.f.u-tokyo.ac.jp.
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002251:Carbon Tetrachloride; D015237:Dinoprost / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D004951:Esterification / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D018390:Gene Targeting; D006868:Hydrolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism; D020002:tert-Butyl Alcohol / Q000494:pharmacology
D010743:Phospholipids; D010972:Platelet Activating Factor; D015237:Dinoprost; D002251:Carbon Tetrachloride; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526455:Pafah2 protein, mouse; D020002:tert-Butyl Alcohol