Abstract 19447: Glycogen Synthase Kinase-3a Regulates Fatty Acid Metabolism Through PPARa Phosphorylation That Underlies Lipotoxic Cardiomyopathy

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Fatty acids are a major energy source for the heart. However, the mechanisms by which fatty acids signal to and balance the cellular metabolism and how disruption of this system induces lipotoxic cardiomyopathy are poorly understood. Using publicly available microarray datasets, we identified glycogen synthase kinase-3a (GSK-3a) as one of the most significantly upregulated kinases in the hearts of genetically obese mice. We verified the upregulation of GSK-3a in diet-induced obese mouse hearts and in cardiomyocytes stimulated with fatty acid using immune-complex in vitro kinase assays. Cardiac-specific haploinsufficiency of GSK-3a, but not GSK-3b, ameliorated diet-induced lipotoxic cardiomyopathy, as evidenced by reduced lipid accumulation, less cardiac hypertrophy and normalized diastolic dysfunction. Gene set enrichment analysis, using microarray data obtained from S21A constitutively active GSK-3a knock-in (KI) mouse hearts, showed that GSK-3a upregulation is sufficient to drive peroxisome proliferator-activated receptor (PPAR) signaling. Immunoprecipitation and mass spectrometry analysis showed that GSK-3a directly interacts with and phosphorylates PPARa at Ser280, located in the ligand-binding domain. This modification enhanced heterodimerization with RXRa and the specific PPRE binding. RNA-seq analysis showed that Ser280-phosphorylation stimulates a subset of PPARa targets independently of ligands, including genes involved in fatty acids uptake and storage, but not catabolism. GC-MS proteomic analysis showed that glucose and BCAA metabolites are similar between WT and the PPARa heterozygous S280A KI mice, whereas a subset of fatty acid metabolites is significantly decreased in the KI mice at baseline. The S280A KI mice conferred resistance to diet-induced cardiomyopathy. Finally, we found that the PPARa ligand fibrates inhibit Ser280-phosphorylation by competing with GSK-3a, thereby reversing lipid-induced PPARa activation and cardiolipotoxicity. These data define an unidentified mechanism for directly regulating fatty acids uptake and storage by GSK-3a depending on fatty acids availability, and indicate that Ser280-phosphorylation may be a novel therapeutic target for lipotoxic cardiomyopathy.

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