Systems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species. [Display omitted] •Lipid modules are associated with phenotypic traits and metabolic pathways•Specific cardiolipin species are associated with healthy or fatty liver signatures•Most lipid species are complex traits, regulated by loci spread across the genome•A new lipid QTL mining pipeline identifies plausible genes regulating lipid species Jha et al. demonstrate the potential of liver lipid species to reflect liver-associated phenotypic metabolic traits in the BXD mouse genetic population. They identify a subset of cardiolipin species—the essential inner mitochondrial membrane phospholipids—that are signatures of healthy or fatty liver. Furthermore, multi-layered omics data (genetic, transcriptomic, proteomic) were employed to filter genes from lipid-regulating loci and provide a resource of candidate genes that may regulate lipid species in mouse and human.