Global Inactivation of the Pla2g6 Gene in Mice Does Not Cause Dyslipidemia under Chow or High-fat Diet Conditions

BACKGROUND: Genome-wide association studies suggest that plasma triacylglyceride (TAG) in humans was associated with variation in the PLA2G6 locus, a gene that encodes calcium-independent phospholipase A(2) (iPLA(2)β). The objective of the present study is to understand the impact of genetic inactivation of iPLA(2)β on hepatic TAG metabolism in C57BL/6 mice. METHODS: Male iPLA(2)β(+)(/−) mice were backcrossed with female iPLA(2)β(−/−) mice for up to 10 generations prior to experiments. Lipid and lipoprotein metabolism from plasma, hepatocytes, thigh subcutaneous adipose and thigh skeletal muscle tissues of the mice were determined under various experimental conditions. RESULTS: The iPLA(2)β(−/−) mice, either male or female as compared with iPLA(2)β(+)(/)(+) littermates, showed no change in fasted or postprandial plasma TAG or total cholesterol at young (12–15 weeks) or old (40–44 weeks) ages under chow diet or high-fat diet (HFD) conditions. However, fractionation of plasma lipoproteins showed that under HFD conditions, there was a significant increase (by 40%) in apoB-100 association with VLDL(1) fractions in iPLA(2)β(−/−) mice as compared with iPLA(2)β(+)(/)(+) littermates. There was no significant difference in triglyceride or cholesterol contents in the liver, muscle, or adipose tissue between iPLA(2)β(−/−) and iPLA(2)β(+/+) littermates. Metabolic labeling experiments with cultured primary hepatocytes isolated from iPLA(2)β(−/−) mice also showed 2-fold increase in the secretion of [(35)S]methionine-labeled apoB-100 in VLDL(1) fractions as compared with that from iPLA(2)β(+)(/)(+) hepatocytes. Likewise, secretion of [(3)H]palmitate-labeled TAG from the iPLA(2)β(−/−) hepatocytes was increased by 2-fold. CONCLUSIONS: Although iPLA(2)β may play a role in TAG-rich VLDL(1) production from cultured hepatocytes, there is no evidence that inactivation of iPLA(2)β would lead to dyslipidemia in mice in vivo.