An integrative systems genetic analysis of mammalian lipid metabolism

• Published in: Nature (London) Vol. 567; no. 7747; pp. 187 - 193
• Main Authors: Parker, Benjamin L., Calkin, Anna C., Seldin, Marcus M., Keating, Michael F., Tarling, Elizabeth J., Yang, Pengyi, Moody, Sarah C., Liu, Yingying, Zerenturk, Eser J., Needham, Elise J., Miller, Matthew L., Clifford, Bethan L., Morand, Pauline, Watt, Matthew J., Meex, Ruth C. R., Peng, Kang-Yu, Lee, Richard, Jayawardana, Kaushala, Pan, Calvin, Mellett, Natalie A., Weir, Jacquelyn M., Lazarus, Ross, Lusis, Aldons J., Meikle, Peter J., James, David E., de Aguiar Vallim, Thomas Q., Drew, Brian G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: 13/109; 38/89; 45/43; 631/443/319; 631/553; 64/60; 82/58; 82/79; Animals; Bioinformatics; Biological markers; Biomarkers; Blood proteins; Chemical compounds; Cholesterol; Datasets; Diagnostic systems; Fatty liver; Genetic analysis; Genetic aspects; Genetic diversity; Genetic research; Genetic testing; Genetic variance; Genomes; Genomics; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Identification; Lipid metabolism; Lipid Metabolism - genetics; Lipid Metabolism - physiology; Lipids; Lipids - analysis; Lipids - blood; Lipids - classification; Lipids - genetics; Liver; Liver - chemistry; Liver - metabolism; Liver - pathology; Localization; Male; Mammals; Medical schools; Metabolic disorders; Metabolic syndrome; Metabolism; Methods; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; multidisciplinary; Musculoskeletal system; Obesity - genetics; Obesity - metabolism; Pathogenesis; Peptides; Pharmacology; Physiological aspects; Plasma; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteins; Proteomics; Science; Science (multidisciplinary); Software
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-0984-y

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. The integration of liver and plasma quantitative lipidomic and proteomic data from 107 distinct mouse strains provides important insights into regulators of mammalian lipid metabolism.