Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits. Jha et al. provide a resource of genetic loci regulating individual plasma lipid species identified by studying a large mouse population and demonstrate the potential of lipid species to reflect metabolic health status of individuals. Several lipid-regulating loci in the mouse population harbor genes associated with abnormal lipid metabolism in human GWAS. The potential of lipid species to reflect health status was validated in dietary and therapeutic models of NAFLD in mice and human NAFLD patients.

Original languageEnglish
Pages (from-to)709-721.e6
JournalCell Systems
Volume6
Issue number6
DOIs
StatePublished - Jun 27 2018

Keywords

  • BXD
  • TAG
  • fatty liver
  • genetic reference population, GRP
  • genetic variation
  • lipid species
  • lipidomics
  • non-alcoholic fatty liver disease, NAFLD
  • quantitative trait locus, QTL
  • steatosis

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