Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/β hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin. PLoS Genet. 2023;19(7):e1010713.
JMG, Animals, Male, Mice, Cardiolipins, Collaborative Cross Mice, Hydrolases, Lipidomics, Phosphatidylcholines, Phospholipids
PLoS Genet. 2023;19(7):e1010713.
This work was supported by grants from the NIH (R01DK101573, R01DK102948, and RC2DK125961 (A.D.A.)) and by the University of Wisconsin–Madison, Department of Biochemistry and Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation (M.P.K.).
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 α/β-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 Abhd2KO 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 Abhd2KO mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids.