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

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

SUBMITTER: Nakamura M 

PROVIDER: S-EPMC6677269 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature