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

Content Provider	Scilit
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
Copyright Year	2019
Description	Journal: Cell Metabolism 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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677269/pdf
e-ISSN	19327420
DOI	10.1016/j.cmet.2019.01.005
Journal	Cell Metabolism
Issue Number	5
Volume Number	29
Language	English
Publisher	Elsevier BV
Publisher Date	2019-02-07
Access Restriction	Open
Subject Keyword	Journal: Cell Metabolism Developmental Biology Fatty Acid Metabolism Lipotoxic Cardiomyopathy Diabetic Cardiomyopathy Lipid Accumulation Metabolic Syndrome
Content Type	Text
Resource Type	Article