| First Author | Nakamura M | Year | 2019 |
| Journal | Cell Metab | Volume | 29 |
| Issue | 5 | Pages | 1119-1134.e12 |
| PubMed ID | 30745182 | Mgi Jnum | J:274681 |
| Mgi Id | MGI:6303393 | Doi | 10.1016/j.cmet.2019.01.005 |
| Citation | Nakamura M, et al. (2019) Glycogen Synthase Kinase-3alpha Promotes Fatty Acid Uptake and Lipotoxic Cardiomyopathy. Cell Metab 29(5):1119-1134.e12 |
| abstractText | Obesity induces lipotoxic cardiomyopathy, a condition in which lipid accumulation in cardiomyocytes causes cardiac dysfunction. Here, we show that glycogen synthase kinase-3alpha (GSK-3alpha) mediates lipid accumulation in the heart. Fatty acids (FAs) upregulate GSK-3alpha, which phosphorylates PPARalpha at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARalpha targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation. Constitutively active GSK-3alpha, but not GSK-3beta, was sufficient to drive PPARalpha signaling, while cardiac-specific knockdown of GSK-3alpha, but not GSK-3beta, or replacement of PPARalpha Ser280 with Ala conferred resistance to lipotoxicity in the heart. Fibrates, PPARalpha ligands, inhibited phosphorylation of PPARalpha at Ser280 by inhibiting the interaction of GSK-3alpha with the LBD of PPARalpha, thereby reversing lipotoxic cardiomyopathy. These results suggest that GSK-3alpha promotes lipid anabolism through PPARalpha-Ser280 phosphorylation, which underlies the development of lipotoxic cardiomyopathy in the context of obesity. |
