Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Identification of a novel regulator of lipid metabolism using a trans-omics approach (#189)

BG Drew 1 , BL Parker 2 , TQ De Aguiar Vallim 3 , MF Keating 1 , M Sekdin 3 , EJ Tarling 3 , SC Moody 1 , EJ Zerenturk 1 , Y Liu 1 , K Jayawardana 1 , NA Mellet 1 , J Weir 1 , C Pan 3 , MA Alameida 4 , JM Peralta 4 , JE Curran 4 , J Blangerro 4 , R Lazarus 1 , AJ Lusis 3 , PJ Meikle 3 , DE James 2 , Anna Calkin 5
  1. Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
  2. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
  3. University of California Los Angeles (UCLA), Los Angeles, CA, USA
  4. University of Texas, Rio Grande Valley , USA
  5. Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia

Background: The liver controls numerous pathways central to the maintenance of whole body lipid metabolism. Dysregulation of these pathways can lead to increased levels of lipids such as cholesterol, triglycerides and diacylglycerols. This can have pathological consequences, promoting the onset of insulin resistance and the development of cardiovascular disease and hepatic steatosis, common complications of diabetes. However, a greater understanding of the pathways mediating this dysregulation is required.

Aims: We used a trans-omics approach combining genomics, phenomics, lipidomics and proteomics to identify novel pathways associated with the regulation of hepatic lipid metabolism. We utilised our exclusive access to a panel of >100 genetically inbred mouse strains, which to our knowledge is the largest and most diverse of its kind in the world, known as the hybrid mouse diversity panel (HMDP) at UCLA.

Methods: We collected livers (n=3) from male mice of 107 HMDP strains that were housed and fed under the same conditions. We performed deep proteomic analysis on livers by performing 34 separate TMT-10 plex multidimensional LC-MS/MS experiments with SPS-MS3 acquisition on an Orbitrap Fusion. We also performed quantitative lipidomics analysis using LC-MS/MS on an AB Sciex API4000 Q/TRAP system on livers and plasma of the same mice.

Results: Proteomic and lipidomics analysis identified numerous hepatic proteins not previously linked to the regulation of lipid metabolism. In particular, we identified a novel protein associated with short-chain saturated diacylglycerols (SCS-DGs), which have been linked to insulin resistance. Interestingly, in vivo adenoviral expression of this target gene was associated with a significant upregulation of these SCS-DGs in various mouse strains. Moreover, this target was associated with onset as well as duration of diabetes in the San Antonio Family Heart Study.

Conclusion: We have established a high-resolution trans-omics network for the identification of novel regulators of hepatic lipid metabolism.