Skeletal Muscle Group VIA Phospholipase A2 (iPLA2β): Expression and Role in Fatty Acid Oxidation

Among the phospholipases A(2) (PLA(2)s) are the group VI Ca2+ independent PLA(2)S (iPLA(2)S), and expression of multiple transcripts of iPLA(2) in skeletal muscle has been reported. In the present study, phospholipase activity and sequential ATP and calmodulin affinity column chromatography analyses reveal that skeletal muscle iPLA(2) exhibits properties characteristic of the iPLA(2)beta isoform. The phospholipase activity of iPLA(2)beta has been demonstrated to participate in signal transduction, cell proliferation, and apoptosis. We report here that skeletal muscle from iPLA(2)beta-null mice, relative to wild-type muscle, exhibits a reduced capacity to oxidize palmitate but not palmitoyl-CoA or acetyl-CoA in the absence of changes in fatty acid transporters CD36 and CPTI or beta-hydroxyacyl-CoA dehydrogenase activity. Recently, purified iPLA(2)beta was demonstrated to manifest a thioesterase activity which catalyzes hydrolysis of fatty acyl-CoAs. The liberated CoA-SH facilitates fatty acid transport into the mitochondria. In this regard, we find that fractions eluted from the ATP column and containing iPLA2 phospholipase activity also contained acyl-CoA thioesterase activity that was inhibited by the bromoenol lactone (BEL) suicide inhibitor of iPLA(2)beta. We further find that acyl-CoA thioesterase activity in skeletal muscle preparations from iPLA(2)beta-null mice is significantly reduced, relative to WT activity. These findings suggest that the absence of acyl-CoA thioesterase activity of iPLA(2)beta can lead to reduced fatty acyl-CoA generation and impair fatty acid oxidation in iPLA(2)beta-null mice. Our findings therefore reveal a novel function of iPLA(2)beta, related not to its phospholipase activity but to its thioesterase activity, which contributes to optimal fatty acid oxidation in skeletal muscle.