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Glycogen Synthase Kinase-3α Promotes Fatty Acid Uptake and Lipotoxic Cardiomyopathy
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February 07 2019
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Source: Cell Metab. 29(5):1119-1134.e12
[PDF-3.08 MB]
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Alternative Title:Cell Metab
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Description: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.
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Pubmed ID:30745182
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Pubmed Central ID:PMC6677269
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Funding:R01 HL102738/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; R01 HL091469/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; R01 HL138720/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; R01 HL067724/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; R01 HL112330/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; ... More +
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Volume:29
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Issue:5
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