Regulation of PAF Acetylhydrolase Expression by Bioactive Lipids

Platelet Activating Factor Acetylhydrolase (PAFAH) is a lipoprotein‐associated phospholipase A 2 (PLA 2 ) that catabolizes platelet‐activating factor (PAF) and PAF‐like, oxidized phospholipids (oxPL) in oxidized LDL (oxLDL). PAFAH is implicated in atherosclerosis although there is debate about whether this enzyme is pro‐ or anti‐atherogenic. Little is known about molecular mechanisms regulating PAFAH expression. PAF induces PAFAH transcription in HEK cells. We hypothesized that PAF‐like, ox‐PL would induce PAFAH expression in monocytes (Mo). Primary Mo were treated with oxLDL, oxPL or PAF. PAFAH was quantified by qPCR, luciferase reporter assay, and a radiometric activity assay. Both oxLDL and oxPL treatment induced PAFAH expression but only in Mo with low basal PAFAH. Unexpectedly, PAF significantly suppressed PAFAH expression and activity, again in Mo with low basal PAFAH. In contrast, a non‐hydrolyzable PAF analog suppressed PAFAH in Mo with both high and low basal PAFAH. These data suggest that PAF and oxLDL regulate PAFAH expression through distinct receptors/signaling mechanisms. As effects of PAF and oxLDL are only observed in Mo with low basal PAFAH, PAF‐like lipids are predicted to be essential for both responses. We are currently identifying receptors, signaling pathways and transcriptional mechanisms by which PAF and oxLDL regulate PAFAH expression. Supported by NIH‐DE13102 and NIH‐DE15980.