Summary of project PR001656

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, where it has been assigned Project ID PR001656. The data can be accessed directly via it's Project DOI: 10.21228/M8ND9B This work is supported by NIH grant, U2C- DK119886.


Project ID: PR001656
Project DOI:doi: 10.21228/M8ND9B
Project Title:Remodeling of lipid landscape in high fat fed very-long chain acyl-CoA dehydrogenase null mice favors pro-arrhythmic polyunsaturated fatty acids and their downstream metabolites
Project Summary:Very-long chain acyl-CoA dehydrogenase (VLCAD) catalyses mitochondrial fatty acid β-oxidation (FAO). Inherited VLCAD deficiency (VLCADD) predisposes to neonatal arrhythmias whose pathophysiology is still not understood. We hypothesized that VLCADD results in global disruption of cardiac complex lipid homeostasis, which may set conditions predisposing to arrhythmia. To test this, we assessed the cardiac lipidome and related molecular markers in seven-month-old VLCAD-/- mice, which mimic to some extent the human cardiac phenotype. Mice were sacrificed in the fed or fasted state after receiving for two weeks a chow or a high-fat diet (HFD), the latter condition being known to worsen symptoms in human VLCADD. Compared to their littermate counterparts, HFD/fasted VLCAD-/- mouse hearts displayed the following lipid alterations: (1) Lower LC, but higher VLC-acylcarnitines accumulation, (2) higher levels of arachidonic acid (AA) and lower docosahexaenoic acid (DHA) contents in glycerophospholipids (GPLs), as well as (3) corresponding changes in pro-arrhythmogenic AA-derived isoprostanes and thromboxane B2 (higher), and anti-arrythmogenic DHA-derived neuroprostanes (lower). These changes were associated with remodeling in the expression of gene or protein markers of (1) PL remodeling: higher calcium-dependent phospholipase A2 and lysophosphatidylcholine-acyltransferase 2, (2) calcium handling perturbations: higher SERCA2a and phospholamban, but lower RyR2, and (3) endoplasmic reticulum stress: higher CHOP and GRP78. Altogether, these results highlight global lipid dyshomeostasis beyond FAO in VLCAD-/- mouse hearts, which may set conditions predisposing the hearts to calcium mishandling and endoplasmic reticulum stress and thereby may contribute to the pathogenesis of arrhythmias in VLCADD in mice as well as in humans.
Institute:Montreal Heart Institute
Last Name:Forest
First Name:Anik
Address:5000 Bélanger Street
Phone:5143763330 ext 2133

Summary of all studies in project PR001656

Study IDStudy TitleSpeciesInstituteAnalysis
(* : Contains Untargted data)
(* : Contains raw data)
ST002569 Lipidomic analysis in very-long chain acyl-CoA dehydrogenase null mice Mus musculus Montreal Heart Institute MS* 2023-09-06 1 39 Uploaded data (7.2G)