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Cell Syst. 2018 Jun 27;6(6):709-721.e6. doi: 10.1016/j.cels.2018.05.009. Epub 2018 Jun 13.

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

Author information

1
Laboratory of Integrative and Systems Physiology, École Polytchnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
2
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
4
Morgridge Institute for Research, Madison, WI 53715, USA.
5
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA.
6
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, USA.
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.
8
Laboratory of Integrative and Systems Physiology, École Polytchnique Fédérale de Lausanne, Lausanne 1015, Switzerland. Electronic address: admin.auwerx@epfl.ch.

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.

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,

PMID:
29909275
DOI:
10.1016/j.cels.2018.05.009
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