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-3 alpha (GSK-3 alpha) mediates lipid accumulation in the heart. Fatty acids (FAs) up-regulate GSK-3 alpha, which phosphorylates PPAR alpha at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPAR alpha targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation. Constitutively active GSK-3 alpha, but not GSK-3 beta, was sufficient to drive PPAR alpha signaling, while cardiac-specific knockdown of GSK-3 alpha, but not GSK-3 beta, or replacement of PPAR alpha Ser280 with Ala conferred resistance to lipotoxicity in the heart. Fibrates, PPAR alpha ligands, inhibited phosphorylation of PPAR alpha at Ser280 by inhibiting the interaction of GSK-3 alpha with the LBD of PPAR alpha, thereby reversing lipotoxic cardiomyopathy. These results suggest that GSK-3 alpha promotes lipid anabolism through PPAR alpha-Ser280 phosphorylation, which underlies the development of lipotoxic cardiomyopathy in the context of obesity.