Identification of a novel noninflammatory biosynthetic pathway of platelet-activating factor.
Platelet-activating factor (PAF) is a potent lipid mediator playing various inflammatory and physiological roles. PAF is biosynthesized through two independent pathways called the de novo and remodeling pathways. Lyso-PAF acetyltransferase (lyso-PAF AT) was believed to biosynthesize PAF under inflammatory conditions, through the remodeling pathway. The first isolated lyso-PAF AT (LysoPAFAT/LPCAT2) had consistent properties. However, we show in this study the finding of a second lyso-PAF AT working under noninflammatory conditions. We partially purified a Ca(2+)-independent lyso-PAF AT from mouse lung. Immunoreactivity for lysophosphatidylcholine acyltransferase 1 (LPCAT1) was detected in the active fraction. Lpcat1-transfected Chinese hamster ovary cells exhibited both LPCAT and lyso-PAF AT activities. We confirmed that LPCAT1 transfers acetate from acetyl-CoA to lyso-PAF by the identification of an acetyl-CoA (and other acyl-CoAs) interacting site in LPCAT1. We further showed that LPCAT1 activity and expression are independent of inflammatory signals. Therefore, these results suggest the molecular diversity of lyso-PAF ATs is as follows: one (LysoPAFAT/LPCAT2) is inducible and activated by inflammatory stimulation, and the other (LPCAT1) is constitutively expressed. Each lyso-PAF AT biosynthesizes inflammatory and physiological amounts of PAF, depending on the cell type. These findings provide important knowledge for the understanding of the diverse pathological and physiological roles of PAF.
Harayama
Takeshi
T
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Shindou
Hideo
H
Ogasawara
Rie
R
Suwabe
Akira
A
Shimizu
Takao
T
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D007249:Inflammation; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D008954:Models, Biological; D010972:Platelet Activating Factor / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D010972:Platelet Activating Factor; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526202:Lpcat1 protein, human; D002118:Calcium