Price Tara R, Stapleton Donnie S, Schueler Kathryn L, Norris Marie K, Parks Brian W, Yandell Brian S, Churchill Gary A, Holland William L, Keller Mark P, Attie Alan D
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT.
bioRxiv. 2023 Mar 24:2023.03.23.533902. doi: 10.1101/2023.03.23.533902.
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 ( ), 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 . The 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 mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids.
我们和其他研究人员之前已经表明，基因关联可用于在基因座与通过质谱法在血液和组织中测量的小分子之间建立因果联系。我们在小鼠7号染色体上确定了一个位点，肝脏中的几种磷脂与不同的基因座显示出很强的基因关联。在本研究中，我们将基因表达数据与基因关联数据相结合，以确定7号染色体位点上的一个单一基因是磷脂表型的驱动因素。该基因编码α/β水解酶结构域2（ABHD2），它是ABHD基因家族23个成员之一。我们通过测量全身缺失ABHD2的小鼠中的脂质来验证这一观察结果。ABHD2基因敲除小鼠肝脏中磷脂酰胆碱和磷脂酰乙醇胺的水平显著升高。出乎意料的是，我们还发现雄性ABHD2基因敲除小鼠中两种关键的线粒体脂质——心磷脂和磷脂酰甘油减少。这些数据表明，ABHD2在肝脏磷脂的合成、周转或重塑中发挥作用。
