Summary of Study ST000429

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000333. The data can be accessed directly via it's Project DOI: 10.21228/M88885 This work is supported by NIH grant, U2C- DK119886.

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Study IDST000429
Study TitleTargeted metabolomics of MuRF1 overexpressing cardiomyocytes compared to their wildtype controls (part I)
Study TypeTargeted metabolomic analysis
Study SummaryThe transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) α by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inhibits fatty acid oxidation by inhibiting PPARα, but not PPARβ/δ or PPARγ in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPARα activity and acyl-carnitine intermediates, while MuRF1−/− hearts exhibited increased PPARα activity and acyl-carnitine intermediates. MuRF1 directly interacts with PPARα, mono-ubiquitinates it, and targets it for nuclear export to inhibit fatty acid oxidation in a proteasome independent manner. We then identified a previously undescribed nuclear export sequence in PPARα, along with three specific lysines (292, 310, 388) required for MuRF1's targeting of nuclear export. These studies identify the role of ubiquitination in regulating cardiac PPARα, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure.
Institute
University of North Carolina at Chapel Hill
DepartmentMcAllister Heart Institute, Department of Internal Medicine
LaboratoryMultiple Centers
Last NameWillis
First NameMonte
Address111 Mason Farm road, Chapel Hill, North Carolina, 27599-7126, USA
Emailmonte_willis@med.unc.edu
Phone919-360-7599
Submit Date2016-07-05
Analysis Type DetailGC-MS
Release Date2016-09-23
Release Version1
Monte Willis Monte Willis
https://dx.doi.org/10.21228/M88885
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000333
Project DOI:doi: 10.21228/M88885
Project Title:The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination
Project Type:Targeted Metabolomics
Project Summary:The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) α by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inhibits fatty acid oxidation by inhibiting PPARα, but not PPARβ/δ or PPARγ in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPARα activity and acyl-carnitine intermediates, while MuRF1−/− hearts exhibited increased PPARα activity and acyl-carnitine intermediates. MuRF1 directly interacts with PPARα, mono-ubiquitinates it, and targets it for nuclear export to inhibit fatty acid oxidation in a proteasome independent manner. We then identified a previously undescribed nuclear export sequence in PPARα, along with three specific lysines (292, 310, 388) required for MuRF1's targeting of nuclear export. These studies identify the role of ubiquitination in regulating cardiac PPARα, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure.
Institute:University of North Carolina at Chapel Hill
Department:McAllister Heart Institute, Department of Internal Medicine
Laboratory:Multiple Centers
Last Name:Willis
First Name:Monte
Address:111 Mason Farm road, Chapel Hill, North Carolina, 27599-7126, USA
Email:monte_willis@med.unc.edu
Phone:919-360-7599
Funding Source:NIH, Fondation Leducq, AHA mid-Atlantic affiliate, AHA scientist development grant, Jefferson-Pilot Corporation Fellowship in Academic Medicine

Subject:

Subject ID:SU000450
Subject Type:Animal
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammal

Factors:

Subject type: Animal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Genotype
SA021659Heart 1WT-MuRF1 tg+
SA021654Heart 6MuRF1 tg+
SA021655Heart 5MuRF1 tg+
SA021656Heart 4MuRF1 tg+
SA021657Heart 2WT-MuRF1 tg+
SA021658Heart 3WT-MuRF1 tg+
Showing results 1 to 6 of 6

Collection:

Collection ID:CO000444
Collection Summary:COS7 and H9C2 cells were transfected with PPRE-luc, pcDNA 3.1, β-galactosidase, and the corresponding PPAR isoform (PPARα, PPARβ/δ or PPARγ) as indicated. 24 hours followings transfection cells were transduced with Ad.GFP-Myc-MuRF1. Cells were harvested 24hours later following observation of GFP by light microscopy
Sample Type:Muscle

Treatment:

Treatment ID:TR000464
Treatment Summary:N/A

Sample Preparation:

Sampleprep ID:SP000457
Sampleprep Summary:Acyl-carnitines were analyzed using stable isotope dilution techniques. Amino acids and acyl-carnitine measurements were made by flow injection tandem mass spectrometry

Combined analysis:

Analysis ID AN000679
Analysis type MS
Chromatography type GC
Chromatography system Waters Acquity
Column Waters ACQUITY UPLC (1.7um)
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5975
Ion Mode POSITIVE
Units uM

Chromatography:

Chromatography ID:CH000491
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC (1.7um)
Chromatography Type:GC

MS:

MS ID:MS000605
Analysis ID:AN000679
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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