| Literature DB >> 26116825 |
Jessica E Rodríguez1, Jie-Ying Liao1, Jun He2, Jonathan C Schisler3, Christopher B Newgard4, Doreen Drujan5, David J Glass5, C Brandon Frederick6, Bryan C Yoder6, David S Lalush6, Cam Patterson7, Monte S Willis8.
Abstract
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.Entities:
Keywords: Cardiac metabolism; Cardiomyocyte; Fatty acid metabolism; Monoubiquitination; Muscle ring finger-1; Peroxisome proliferator-activated receptor α
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Year: 2015 PMID： 26116825 PMCID： PMC4523404 DOI： 10.1016/j.mce.2015.06.008
Source DB: PubMed Journal: Mol Cell Endocrinol ISSN： 0303-7207 Impact factor: 4.102