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Abstract 343: Novel Regulation of Cholesterol Metabolism Using a Systems Biology Approach
13 auth. Benjamin L. Parker, T. Vallim, M. Seldin, Michael F. Keating, E. Tarling, Eser J. Zerenturk, Sarah C. Moody, Yingying Liu, Peter J. Meikle, A. Lusis, ...
Background:
Dysregulation of lipid homeostasis promotes metabolic diseases including fatty liver disease and cardiovascular disease. We have successfully used a trans-omics approach across a genetic reference panel of mice to identify novel regul…
Background:
Dysregulation of lipid homeostasis promotes metabolic diseases including fatty liver disease and cardiovascular disease. We have successfully used a trans-omics approach across a genetic reference panel of mice to identify novel regulators of acylglycerol metabolism. Here, we utilise this approach to interrogate hepatic cholesterol metabolism.
Methods:
We utilised >100 genetically distinct mouse strains, collectively known as the hybrid mouse diversity panel (HMDP) at UCLA. Livers from male mice of 107 HMDP strains that were all housed and fed under the same conditions were collected (n=2-3/strain). Deep proteomic analysis (34 separate TMT-10 plex multidimensional LC-MS/MS experiments, SPS-MS3 acquisition on an Orbitrap Fusion) and quantitative lipidomics (LC-MS/MS on an AB Sciex API4000 Q/TRAP system) was performed. This approach quantified >7,000 proteins in liver and >300 lipid species across 23 lipid classes in livers and plasma of HMDP mice.
Results:
Cholesterol esters varied 11-fold and 3-fold in liver and plasma of mice, respectively. Weighted correlation network analysis revealed mitochondrial pathways were most positively associated, and ribosomal pathways most negatively associated with hepatic CE accumulation. Cyp51, msmo1 and idi1 were amongst the proteins most negatively associated with hepatic CE accumulation along with some novel targets. Moreover, seed mapping using Cyp51 mapped the cholesterol biosynthetic pathway with high fidelity but also revealed novel proteins associated with cholesterol metabolism. I
n vitro
and
in vivo
ectopic expression of such targets revealed modulation of plasma and liver CE levels as well as key regulators of cholesterol metabolism such as HMGCR and ABCAI.
Conclusions:
We have established a high-resolution trans-omics network for the identification of novel regulators of lipid metabolism. We have validated this approach to identify
bone fide
regulators of cholesterol metabolism.
Published in
Arteriosclerosis, Thrombosis and Vascular Biology
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