An integrative systems genetic analysis of mammalian lipid metabolism

Benjamin L. Parker, Anna C. Calkin (), Marcus M. Seldin, Michael F. Keating, Elizabeth J. Tarling, Pengyi Yang, Sarah C. Moody, Yingying Liu, Eser J. Zerenturk, Elise J. Needham, Matthew L. Miller, Bethan L. Clifford, Pauline Morand, Matthew J. Watt, Ruth C. R. Meex, Kang-Yu Peng, Richard Lee, Kaushala Jayawardana, Calvin Pan, Natalie A. Mellett, Jacquelyn M. Weir, Ross Lazarus, Aldons J. Lusis, Peter J. Meikle, David E. James, Thomas Q. Aguiar Vallim () and Brian G. Drew ()
Additional contact information
Benjamin L. Parker: University of Sydney
Anna C. Calkin: Baker Heart & Diabetes Institute
Marcus M. Seldin: University of California Los Angeles (UCLA)
Michael F. Keating: Baker Heart & Diabetes Institute
Elizabeth J. Tarling: University of California Los Angeles (UCLA)
Pengyi Yang: University of Sydney
Sarah C. Moody: Baker Heart & Diabetes Institute
Yingying Liu: Baker Heart & Diabetes Institute
Eser J. Zerenturk: Baker Heart & Diabetes Institute
Elise J. Needham: University of Sydney
Matthew L. Miller: University of California Los Angeles (UCLA)
Bethan L. Clifford: University of California Los Angeles (UCLA)
Pauline Morand: University of California Los Angeles (UCLA)
Matthew J. Watt: University of Melbourne
Ruth C. R. Meex: University of Melbourne
Kang-Yu Peng: Baker Heart & Diabetes Institute
Richard Lee: Ionis Therapeutics Inc.
Kaushala Jayawardana: Baker Heart & Diabetes Institute
Calvin Pan: University of California Los Angeles (UCLA)
Natalie A. Mellett: Baker Heart & Diabetes Institute
Jacquelyn M. Weir: Baker Heart & Diabetes Institute
Ross Lazarus: Baker Heart & Diabetes Institute
Aldons J. Lusis: University of California Los Angeles (UCLA)
Peter J. Meikle: Baker Heart & Diabetes Institute
David E. James: University of Sydney
Thomas Q. Aguiar Vallim: University of California Los Angeles (UCLA)
Brian G. Drew: Monash University

Nature, 2019, vol. 567, issue 7747, 187-193

Abstract: Abstract Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.

Date: 2019
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DOI: 10.1038/s41586-019-0984-y

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