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

Pooja Jha, Molly T. McDevitt, Rahul Gupta, Pedro M. Quiros, Evan G. Williams, Karim Gariani, Maroun B. Sleiman, Leo Diserens, Adam Jochem, Arne Ulbrich, Joshua J. Coon, Johan Auwerx, David J. Pagliarini

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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. 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.

Original languageEnglish
Pages (from-to)722-733.e6
JournalCell Systems
Volume6
Issue number6
DOIs
StatePublished - Jun 27 2018

Keywords

  • BXD
  • cardiolipin
  • fatty liver
  • genetic reference population, GRP
  • genetic variation
  • genome-wide association study, GWAS
  • lipid species
  • lipidomics
  • non-alcoholic fatty liver disease, NAFLD
  • quantitative trait locus, QTL

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