Using an omics approach to identify novel regulators of hepatic lipid metabolism

Drew BG1, Parker BL2, Seldin M3, Keating MF1, Meikle PJ1, Tarling EJ3, Lusis AJ3, James DJ2, De Aguiar Vallim TQ3 and Calkin AC1

  1. Baker Heart and Diabetes Institute.
  2. Charles Perkins Centre, University of Sydney.
  3. University of California, Los Angeles.

Background: The liver controls numerous pathways central to the maintenance of whole body lipid metabolism. Dysregulation of these pathways can result in increased levels of pathological lipids that can promote insulin resistance, fatty liver disease and cardiovascular disease. Thus, we need a greater understanding of the pathways regulating hepatic lipid metabolism. Methods: We utilised a trans-omics approach to analyse mouse livers across 100+ strains of genetically diverse mice, integrating genetics, phenomics, and proteomics (>8000 proteins; Orbitrap Fusion) as well as liver and plasma lipidomics (>300 lipids; API4000 Q/TRAP) to identify novel lipid signatures and pathways associated with metabolic diseases. Results: This approach has generated a powerful platform that we can interrogate to perform protein:protein correlations, which can give us insight into protein complexes and protein localisation within the cell; protein:lipid correlations, which can provide insight into novel regulators of known pathological lipids; lipid:lipid correlations, which can provide an avenue to identify plasma lipids that might predict hepatic accumulation of known pathological lipids linked to metabolic disease. Findings are validated in vitro, in preclinical models and in clinical cohorts such as the UK Biobank and the San Antonio Family Heart Study. Conclusions: We have established a high-resolution trans-omics platform for the identification of novel regulators of hepatic lipid metabolism, with implications for therapeutic intervention of metabolic diseases.