Format

Send to

Choose Destination
Nature. 2019 Mar;567(7747):187-193. doi: 10.1038/s41586-019-0984-y. Epub 2019 Feb 27.

An integrative systems genetic analysis of mammalian lipid metabolism.

Author information

1
Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia.
2
Lipid Metabolism & Cardiometabolic Disease Laboratory, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia. anna.calkin@baker.edu.au.
3
Central Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia. anna.calkin@baker.edu.au.
4
Department of Human Genetics/Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
5
Lipid Metabolism & Cardiometabolic Disease Laboratory, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
6
Central Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
7
Molecular Metabolism & Ageing Laboratory, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
8
Department of Medicine, Division of Cardiology, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
9
Molecular Biology Institute, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
10
Charles Perkins Centre, School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia.
11
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
12
Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.
13
Metabolomics Laboratory, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
14
Ionis Therapeutics Inc., Carlsbad, CA, USA.
15
Department of Medicine, Division of Cardiology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. tvallim@mednet.ucla.edu.
16
Molecular Biology Institute, University of California Los Angeles (UCLA), Los Angeles, CA, USA. tvallim@mednet.ucla.edu.
17
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA. tvallim@mednet.ucla.edu.
18
Central Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia. brian.drew@baker.edu.au.
19
Molecular Metabolism & Ageing Laboratory, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia. brian.drew@baker.edu.au.

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.

PMID:
30814737
DOI:
10.1038/s41586-019-0984-y

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center