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Cell Syst. 2018 Jun 27;6(6):722-733.e6. doi: 10.1016/j.cels.2018.05.016. Epub 2018 Jun 13.

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

Author information

1
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
2
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Morgridge Institute for Research, Madison, WI 53715, USA.
4
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
5
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
6
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.
7
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: dpagliarini@morgridge.org.

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.

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

PMID:
29909277
PMCID:
PMC6054463
DOI:
10.1016/j.cels.2018.05.016
[Indexed for MEDLINE]
Free PMC Article

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