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Muscle ring finger‐1 (MuRF1) regulates cardiac fatty acid and glucose metabolism via its interaction with PPARα
Author(s) -
Rodriguez Jessica E.,
Li Luge,
Willis Monte S.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.38.3
Subject(s) - ring finger , peroxisome , peroxisome proliferator activated receptor , chemistry , ubiquitin ligase , beta oxidation , fatty acid , nuclear receptor , ubiquitin , transcription factor , receptor , response element , cardiac muscle , reporter gene , biochemistry , microbiology and biotechnology , endocrinology , gene expression , biology , gene , promoter
We recently identified that increasing the cardiac ubiquitin ligase Muscle Ring Finger‐1 (MuRF1) levels in cardiomyocytes experimentally resulted in a dose‐dependent inhibition of fatty acid oxidation and parallel increase in glucose oxidation. Since these changes in substrate utilization parallel those that occur during cardiac hypertrophy development, we set out to determine how MuRF1 regulated the members of the peroxisome proliferator‐activated receptor (PPAR) transcription factor family. Cardiomyocytes were co‐transfected with PPAR expression constructs, PPAR‐response element (PPRE)‐activity reporter constructs, and MuRF1. MuRF1 specifically inhibited PPARα activity (over 5 fold). MuRF1 transgenic hearts demonstrated decreases in PPARα activity detected by a decrease in PPAR bound to nuclear PPAR‐response elements. By immunoprecipitating MuRF1 or endogenous PPARα from cardiomyocytes, we identified specific binding of the reciprocal protein (PPARα or MuRF1, respectively). MuRF1 over‐expression displaced nuclear PPARα compared to adenovirus control cells by immunofluorescence. These studies identify a novel mechanism by which cardiac hypertrophy driven increases in MuRF1 might regulate characteristic decreases in fatty acid oxidation and increases in glucose oxidation by its post‐translational modification of PPARα to affect subcellular localization.