Abstract 13671: GSK-3α Directly Regulates Lipid Metabolism Through Obesity-linked Phosphorylation of PPARα
Obesity impairs lipid metabolism and leads to cardiac dysfunction, where peroxisome proliferator-activated receptor α (PPARα) serves as a key regulator of lipid metabolism. Glycogen synthase kinase-3α (GSK-3α), a serine-threonine kinase, is markedly upregulated in the heart of obese mice, suppressing glycogen synthesis. However, the functional significance of upregulated GSK-3α in lipid metabolism remains unknown. Here we show that GSK-3α directly upregulates lipid metabolism and aggravates cardiac lipotoxicity in obesity. GSK-3α activity was enhanced by palmitic acid (PA) in the nucleus in cardiomyocytes (CMs), and knockdown of GSK-3α suppressed PA-induced activation of PPARα. GSK-3α, but not GSK-3β, directly interacted with PPARα. Mass spectrometry analysis revealed that GSK-3α phosphorylates PPARα at Ser280, located in the ligand binding domain. A PPARα phospho-mimicking mutant (PPARα-S280D) exhibited an increase in both the interaction of PPARα with RXR and its DNA binding, enhancing PPARα activity and stimulating expression of lipid metabolism-related genes, including Cpt1b, CD36 and PDHK4, in CMs. High-fat diet (HFD)-fed mice displayed increased GSK-3α activity and PPARα phosphorylation in the heart. Cardiac-specific haploinsufficiency of GSK-3α normalized HFD-induced lipid accumulation (Oil Red O staining), abnormally enhanced palmitate oxidation (0.82 fold, p<0.05), cardiac hypertrophy and diastolic dysfunction (0.36 fold in EDPVR, p<0.05) without affecting body weight gain or food intake. While adenovirus-mediated overexpression of PPARα in the heart exacerbated HFD-induced lipid dysregulation and cardiac dysfunction, that of PPARα phospho-resistant mutant (PPARα-S280A) failed to facilitate lipid metabolism and cardiac dysfunction in the presence of a HFD. Notably, a PPARα ligand, fenofibrate, allosterically inhibited PPARα phosphorylation in obese mice by interfering with the interaction between GSK-3α and PPARα, and improved HFD-induced lipid accumulation and cardiac dysfunction. These data show that GSK-3α directly regulates lipid metabolism through Ser280 phosphorylation of PPARα, and that its phosphorylation could be a novel therapeutic target for obesity-related cardiac dysfunction.
Author Disclosures: M. Nakamura: None. P. Zhai: None. T. Liu: None. H. Li: None. J. Sadoshima: None.
- © 2015 by American Heart Association, Inc.