ArticleCell metabolism2019
Glycogen Synthase Kinase-3α Promotes Fatty Acid Uptake and Lipotoxic Cardiomyopathy.
Article in Cell metabolism, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 110 citations in OpenAlex.
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- Farnesyltransferase Deficiency in Cardiomyocytes Initiates Senescence and Contributes to Cardiac Fibrosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PPARα-NF-κB heterodimer mediates obesity-induced diastolic dysfunction through autocrine production of IL-6.The Journal of clinical investigation · 2026Article
- Role of GSK-3 Inhibition in Alzheimer's Disease Therapy.Current Alzheimer research · 2026Review
- Calcium Signaling Dysregulation in Diabetic Cardiomyopathy: Roles of STIM and Orai Channels.Handbook of experimental pharmacology · 2026Review
- The Synergistic Role of ApoE4 and GSK3β in Alzheimer's Disease: Pathological Mechanisms and Therapeutic Implications.Molecular neurobiology · 2025Review
- Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.Journal of the American Heart Association · 2025Article
- KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart.Molecular metabolism · 2025Article
- Reprogramming of Mitochondrial and Cellular Energy Metabolism in Fibroblasts and Cardiomyocytes: Mechanisms and Therapeutic Strategies in Cardiac Fibrosis.Journal of cardiovascular translational research · 2025Review
- Article
- GSK-3α regulates miRNAs associated with transcriptional and metabolic processes in human cardiomyocytes under hypoxia.The Biochemical journal · 2025Article
- MAPK, PI3K/Akt Pathways, and GSK-3β Activity in Severe Acute Heart Failure in Intensive Care Patients: An Updated Review.Journal of cardiovascular development and disease · 2025Review
- Protective effect of Dan Ze mixture against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway.Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan · 2025Article
- Cardiac substrate metabolism in type 2 diabetes.The Biochemical journal · 2025Review
- Advances in nanotechnology for the diagnosis and management of metabolic dysfunction-associated steatotic liver disease.Asian journal of pharmaceutical sciences · 2025Review
- Exploring the Multifaceted Metabolic Pathology and Mechanisms of NAFLD: A Bibliometric Analysis and an In-depth Review.Current pharmaceutical design · 2025Review
- Lysozyme supplement enhances antioxidant capacity and regulates liver glucolipid metabolism in weaned piglets.Frontiers in veterinary science · 2025Article
- Unraveling mitochondrial crosstalk: a new frontier in heart failure pathogenesis.Frontiers in cardiovascular medicine · 2025Review
- Intermedin Alleviates Diabetic Cardiomyopathy by Up-Regulating CPT-1β through Activation of the Phosphatidyl Inositol 3 Kinase/Protein Kinase B Signaling Pathway.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.iScience · 2024Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.