Lipidomic QTL in Diversity Outbred mice identifies a novel function for / hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin

We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this study, we integrated gene expression data with genetic association data to identify a single gene at the chromosome 7 locus as the driver of the phospholipid phenotypes. The gene encodes & alpha;/& beta;-hydrolase domain 2 (Abhd2), one of 23 members of the ABHD gene family. We validated this observation by measuring lipids in a mouse with a whole-body deletion of Abhd2. The Abhd2(KO) mice had a significant increase in liver levels of phosphatidylcholine and phosphatidylethanolamine. Unexpectedly, we also found a decrease in two key mitochondrial lipids, cardiolipin and phosphatidylglycerol, in male Abhd2(KO) mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids. Author summaryLipids have broad roles in normal physiology and disruptions to lipid metabolism have been linked to disease development; new roles for the enzymes that metabolize lipids are still being discovered. To identify novel genes associated with a wide array of liver lipids, we conducted a genetic screen of untargeted liver lipidomics in a genetically diverse mouse population. We identified the enzyme, Abhd2, as a candidate driver of multiple liver phospholipids. Further, we validated Abhd2 in a whole-body knockout mouse model, where loss of Abhd2 resulted in increased liver phosphatidylcholine and a marked decrease in the mitochondrial lipids, cardiolipin and phosphatidylglycerol. Thus, the genetic screen and in vivo validation enabled us to discover a previously unknown role Abhd2 in regulating liver phospholipids, including those associated with mitochondrial membranes. Our study highlights the power of lipid genetic screens to nominate and identify novel substrates for enzymes and their larger role in physiology.