Summary of Study ST000430
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.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST000430 |
| Study Title | Targeted metabolomics of MuRF1 Knockdown cardiomyocytes compared to their wildtype controls (part II) |
| Study Type | Targeted metabolomic analysis |
| Study 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 |
| monte_willis@med.unc.edu | |
| Phone | 919-360-7599 |
| Submit Date | 2016-07-05 |
| Analysis Type Detail | GC-MS |
| Release Date | 2016-09-23 |
| Release Version | 1 |
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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: | SU000451 |
| 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 |
|---|---|---|
| SA021660 | M1KO H7 (21) | KO |
| SA021661 | M1KO H8 (22) | KO |
| SA021662 | M1KO H6 (20) | KO |
| SA021663 | M1KO H5 (19) | KO |
| SA021664 | M1KO H2 (16) | WT |
| SA021665 | M1KO H3 (17) | WT |
| SA021666 | M1KO H4 (18) | WT |
| SA021667 | M1KO H1 (15) | WT |
| Showing results 1 to 8 of 8 |
Collection:
| Collection ID: | CO000445 |
| 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: | TR000465 |
| Treatment Summary: | N/A |
Sample Preparation:
| Sampleprep ID: | SP000458 |
| 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 | AN000680 |
|---|---|
| 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: | CH000492 |
| Instrument Name: | Waters Acquity |
| Column Name: | Waters ACQUITY UPLC (1.7um) |
| Chromatography Type: | GC |
MS:
| MS ID: | MS000606 |
| Analysis ID: | AN000680 |
| Instrument Name: | Agilent 5975 |
| Instrument Type: | Single quadrupole |
| MS Type: | EI |
| Ion Mode: | POSITIVE |
