Activation of Sphingolipid Pathway in the Livers of Lipodystrophic Agpat2(−/−) Mice

A several fold increase in triacylglycerol is observed in the livers of lipodystrophic Agpat2(−/−) mice. We have previously reported an unexpected increase in the phosphatidic acid (PA) levels in the livers of these mice and that a few specific molecular species of PA were able to transcriptionally upregulate hepatic gluconeogenesis. In the current study, we measured the metabolites and expression of associated enzymes of the sphingolipid synthesis pathway. The entire sphingolipid pathway was activated both at the gene expression and the metabolite level. The levels of some ceramides were increased by as much as ~eightfold in the livers of Agpat2(−/−) mice. Furthermore, several molecular species of ceramides were increased in the plasma of Agpat2(−/−) mice, specifically ceramide C16:0, which was threefold elevated in the plasma of both the sexes. However, the ceramides failed to increase glucose production in mouse primary hepatocytes obtained from wild-type and Agpat2(−/−) mice, further establishing the specificity of PA in the induction of hepatic gluconeogenesis. This study shows elevated levels of sphingolipids in the steatotic livers of Agpat2(−/−) mice and increased expression of associated enzymes for the sphingolipid pathway. Therefore, this study and those in the literature suggest that ceramide C16:0 could be used as a biomarker for insulin resistance/type 2 diabetes mellitus.