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

Details

• Alternative Title:
  Cell Metab
• Personal Author:
  Nakamura, Michinari ; Liu, Tong ; Husain, Seema ; Zhai, Peiyong ; Warren, Junco S. ; Hsu, Chiao-Po ; Matsuda, Takahisa ; Phiel, Christopher J. ; Cox, James E. ; Tian, Bin ; Li, Hong ; Sadoshima, Junichi
• 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.
• Subjects:
  Article Fatty Acid Metabolism Fibrates GSK-3α Lipotoxic Cardiomyopathy Obesity PPARα
• Source:
  Cell Metab. 29(5):1119-1134.e12
• Pubmed ID:
  30745182
• Pubmed Central ID:
  PMC6677269
• Document Type:
  Journal Article
• 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 ; S10 OD021505/ODCDC CDC HHS/Office of the Director/United States ; R01 AG023039/NIA NIH HHS/National Institute on Aging/United States
• Volume:
  29
• Issue:
  5
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f49479eef1ae8b76584103128586ef4f67cb944448cbb669180f1c5be0eed24d
• Download URL:
  https://stacks.cdc.gov/view/cdc/80410/cdc_80410_DS1.pdf
• File Type:
  [PDF - 3.08 MB ]