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

ABSTRACT: Obesity induces lipotoxic cardiomyopathy, a condition in which lipid accumulation in cardiomyocytes causes cardiac dysfunction. Here, we show that glycogen synthase kinase-3? (GSK-3?) mediates lipid accumulation in the heart. Fatty acids (FAs) upregulate GSK-3?, which phosphorylates PPAR? at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPAR? targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation. Constitutively active GSK-3?, but not GSK-3?, was sufficient to drive PPAR? signaling, while cardiac-specific knockdown of GSK-3?, but not GSK-3?, or replacement of PPAR? Ser280 with Ala conferred resistance to lipotoxicity in the heart. Fibrates, PPAR? ligands, inhibited phosphorylation of PPAR? at Ser280 by inhibiting the interaction of GSK-3? with the LBD of PPAR?, thereby reversing lipotoxic cardiomyopathy. These results suggest that GSK-3? promotes lipid anabolism through PPAR?-Ser280 phosphorylation, which underlies the development of lipotoxic cardiomyopathy in the context of obesity.

SUBMITTER: Nakamura M

PROVIDER: S-EPMC6677269 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Nakamura Michinari M Liu Tong T Husain Seema S Zhai Peiyong P Warren Junco S JS Hsu Chiao-Po CP Matsuda Takahisa T Phiel Christopher J CJ Cox James E JE Tian Bin B Li Hong H Sadoshima Junichi J

Cell metabolism 20190207 5

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, thereb ...[more]

PMID: 30745182

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Project description:BackgroundCyclophilin D (CypD) negatively regulates ATP production by opening of the mitochondrial permeability transition pore. This study aimed to understand the role of CypD in sperm motility regulation.MethodsChanges in CypD during sperm capacitation and its interaction with glycogen synthase kinase 3α (GSK3α), a key kinase regulating sperm motility, were examined in mouse spermatozoa. The effects of CypD inhibitor cyclosporin A (CsA) and GSK3 inhibitor 6-bromo-indirubin-3'-oxime (BIO) on sperm motility, p-GSK3α(Ser21), mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP), and ATP production were examined. The effect of proteasome inhibitor MG115 on the cellular levels of CypD was examined.ResultsIn cauda epididymal spermatozoa, GSK3α was found in both cytosolic and mitochondrial fractions whereas CypD was primarily found in the mitochondrial fraction together with ATP synthase F1 subunit alpha (ATP5A), a mitochondrial marker. GSK3α and CypD were co-localized in the sperm midpiece. Interaction between GSK3α and CypD was identified in co-immunoprecipitation. CsA, a CypD inhibitor, significantly increased sperm motility, tyrosine phosphorylation, mPTP closing, MMP, and ATP levels in spermatozoa, suggesting that CypD acts as a negative regulator of sperm function. Under capacitation condition, both GSK3α and CypD were decreased in spermatozoa but ATP5A was not. The GSK3 inhibitor BIO markedly increased p-GSK3α(Ser21) and decreased CypD but significantly increased mPTP closing, MMP, ATP production, and motility of spermatozoa. This suggests that inhibitory phosphorylation of GSK3α is coupled with degradation of CypD, potentiating the mitochondrial function. Degradation of CypD was attenuated by MG115, indicative of involvement of the ubiquitin proteasome system.ConclusionsDuring sperm capacitation, CypD act as a downstream target of GSK3α can be degraded via the ubiquitin proteasome system, stimulating mitochondrial function and sperm motility.

Dataset Information

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

Publications

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

Similar Datasets

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