Glycogen Synthase Kinase-3α Promotes Fatty Acid Uptake and Lipotoxic Cardiomyopathy

Obesity induces lipotoxic cardiomyopathy, a condition in which lipid accumulation in cardiomyocytes causes cardiac dysfunction. Here, we show that glycogen synthase kinase-3α (GSK-3α) mediates lipid accumulation in the heart. Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation. Constitutively active GSK-3α, but not GSK-3β, was sufficient to drive PPARα signaling, while cardiac-specific knockdown of GSK-3α, but not GSK-3β, or replacement of PPARα Ser280 with Ala conferred resistance to lipotoxicity in the heart. Fibrates, PPARα ligands, inhibited phosphorylation of PPARα at Ser280 by inhibiting the interaction of GSK-3α with the LBD of PPARα, thereby reversing lipotoxic cardiomyopathy. These results suggest that GSK-3α promotes lipid anabolism through PPARα-Ser280 phosphorylation, which underlies the development of lipotoxic cardiomyopathy in the context of obesity. [Display omitted] •Fatty acids upregulate GSK-3α, which in turn phosphorylates PPARα at Ser280•Ser280 phosphorylation stimulates biased gene expression, favoring fatty acid uptake•PPARα-Ser280 phosphorylation promotes the development of lipotoxic cardiomyopathy•Fibrates inhibit Ser280 phosphorylation, thereby reversing cardiac lipotoxicity Nakamura et al. investigate the mechanisms underlying the development of lipotoxic cardiomyopathy. Fatty-acid-induced upregulation of GSK-3α acts as a central regulator of cardiac fatty acid metabolism by stimulating a biased PPARα transcriptional response via Ser280 phosphorylation, favoring fatty acid uptake. A reversal of Ser280 phosphorylation attenuates lipotoxicity.