Heart-Type Fatty Acid Binding Protein Binds Long-Chain Acylcarnitines and Protects against Lipotoxicity

Heart-type fatty-acid binding protein (FABP3) is an essential cytosolic lipid transport protein found in cardiomyocytes. FABP3 binds fatty acids (FAs) reversibly and with high affinity. Acylcarnitines (ACs) are an esterified form of FAs that play an important role in cellular energy metabolism. However, an increased concentration of ACs can exert detrimental effects on cardiac mitochondria and lead to severe cardiac damage. In the present study, we evaluated the ability of FABP3 to bind long-chain ACs (LCACs) and protect cells from their harmful effects. We characterized the novel binding mechanism between FABP3 and LCACs by a cytotoxicity assay, nuclear magnetic resonance, and isothermal titration calorimetry. Our data demonstrate that FABP3 is capable of binding both FAs and LCACs as well as decreasing the cytotoxicity of LCACs. Our findings reveal that LCACs and FAs compete for the binding site of FABP3. Thus, the protective mechanism of FABP3 is found to be concentration dependent.

• Publication year

  2023

• Venue

  International Journal of Molecular Sciences

• Publication date

  2023-03-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.3390/ijms24065528PMID 36982599PMCID 10058761
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The measurement of binding affinities by NMR chemical shift perturbation

  2022cited by this paper
• Excited-state intermediates in a designer protein encoding a phototrigger caught by an X-ray free-electron laser

  2022cited by this paper
• Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials

  2022cited by this paper
• Too complex to fail? Targeting fatty acid metabolism for cancer therapy.

  2021cited by this paper
• Low cardiac content of long-chain acylcarnitines in TMLHE knockout mice prevents ischaemia-reperfusion-induced mitochondrial and cardiac damage.

  2021cited by this paper
• Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury.

  2021cited by this paper
• Long-Chain Acylcarnitines Decrease the Phosphorylation of the Insulin Receptor at Tyr1151 Through a PTP1B-Dependent Mechanism

  2021cited by this paper
• Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment

  2020cited by this paper
• Long-Chain Acylcarnitines and Cardiac Excitation-Contraction Coupling: Links to Arrhythmias

  2020cited by this paper
• A new methodology to assess the solubility of fatty acids: Impact of food emulsifiers.

  2020influential reference
• Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases

  2019cited by this paper
• Fatty acid oxidation disorders.

  2018cited by this paper
• Lipids in the cell: organisation regulates function

  2018cited by this paper
• Lipid metabolism in inflammation-related diseases.

  2018cited by this paper
• Heat Capacity Changes for Transition-State Analogue Binding and Catalysis with Human 5'-Methylthioadenosine Phosphorylase.

  2017cited by this paper
• Long-chain acylcarnitines determine ischaemia/reperfusion-induced damage in heart mitochondria.

  2016cited by this paper
• Acylcarnitines—old actors auditioning for new roles in metabolic physiology

  2015cited by this paper
• The heart is better protected against myocardial infarction in the fed state compared to the fasted state.

  2014cited by this paper
• Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria

  2014cited by this paper
• Crystallographic study of FABP5 as an intracellular endocannabinoid transporter.

  2014cited by this paper
• Water-Mediated Recognition of Simple Alkyl Chains by Heart-Type Fatty-Acid-Binding Protein

  2014influential reference
• Using chemical shift perturbation to characterise ligand binding.

  2013cited by this paper
• The human fatty acid-binding protein family: Evolutionary divergences and functions

  2011cited by this paper
• The multigene family of fatty acid-binding proteins (FABPs): Function, structure and polymorphism

  2010cited by this paper
• X‐ray crystallographic analysis of adipocyte fatty acid binding protein (aP2) modified with 4‐hydroxy‐2‐nonenal

  2010cited by this paper
• Rapid determination of surfactant critical micelle concentrations using pressure-driven flow with capillary electrophoresis instrumentation.

  2009cited by this paper
• Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation.

  2009cited by this paper
• Expression and purification of soluble His(6)-tagged TEV protease.

  2009cited by this paper
• Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets

  2008influential reference
• Different effects of palmitoyl-L-carnitine and palmitoyl-CoA on mitochondrial function in rat ventricular myocytes.

  2008cited by this paper
• Synthesis of Carnitine Benzyl Esters as Prodrugs

  2008cited by this paper
• Structural basis for activation of fatty acid-binding protein 4.

  2007cited by this paper
• Inflammation and metabolic disorders

  2006cited by this paper
• Enthalpy-entropy compensation is not a general feature of weak association.

  2005cited by this paper
• The Computer Aided Resonance Assignment Tutorial

  2004cited by this paper
• Role of fatty acid-binding protein in cardiac fatty acid oxidation

  2004cited by this paper
• Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection.

  2003cited by this paper
• Fatty acid oxidation disorders.

  2002cited by this paper
• Interactions of acyl carnitines with model membranes DOI 10.1194/jlr.M200137-JLR200

  2002cited by this paper
• Thermodynamic analysis of the binding of component enzymes in the assembly of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus

  2002cited by this paper
• New insights into the structure and function of fatty acid-binding proteins

  2002cited by this paper
• Thermodynamic Quantities for the Ionization Reactions of Buffers

  2002cited by this paper
• Entropy—enthalpy compensation: Fact or artifact?

  2001cited by this paper
• Ligand specificity and conformational stability of human fatty acid-binding proteins.

  2001cited by this paper
• Spin-system heterogeneities indicate a selected-fit mechanism in fatty acid binding to heart-type fatty acid-binding protein (H-FABP).

  2001cited by this paper
• Insulin signalling and the regulation of glucose and lipid metabolism

  2001cited by this paper
• Studies of the ligand binding reaction of adipocyte lipid binding protein using the fluorescent probe 1, 8-anilinonaphthalene-8-sulfonate.

  1999cited by this paper
• Requirement for the heart‐type fatty acid binding protein in cardiac fatty acid utilization

  1999cited by this paper
• Impaired long-chain fatty acid utilization by cardiac myocytes isolated from mice lacking the heart-type fatty acid binding protein gene.

  1999cited by this paper
• Muscle fatty acid-binding protein.

  1999cited by this paper
• Three-dimensional structure of bovine heart fatty-acid-binding protein with bound palmitic acid, determined by multidimensional NMR spectroscopy.

  1995cited by this paper
• Lethal neonatal deficiency of carnitine palmitoyltransferase II associated with dysgenesis of the brain and kidneys.

  1995cited by this paper
• Heart fatty acid binding protein is a novel regulator of cardiac myocyte hypertrophy.

  1994cited by this paper
• X-ray crystallographic structures of adipocyte lipid-binding protein complexed with palmitate and hexadecanesulfonic acid. Properties of cavity binding sites.

  1994cited by this paper
• The adipocyte lipid-binding protein at 1.6-A resolution. Crystal structures of the apoprotein and with bound saturated and unsaturated fatty acids.

  1994cited by this paper
• Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids.

  1994influential reference
• Three-dimensional structure of the muscle fatty-acid-binding protein isolated from the desert locust Schistocerca gregaria.

  1994cited by this paper
• Cytoplasmic fatty acid binding protein: significance for intracellular transport of fatty acids and putative role on signal transduction pathways.

  1993cited by this paper
• Synthesis and preliminary evaluation of perfluoroalkylacyl carnitines as surfactants for biomedical use

  1991cited by this paper
• Two‐dimensional electrophoresis of the fatty acid binding protein from human heart: Evidence for a thiol group which can form an intermolecular disulfide bond

  1990cited by this paper
• Characterization and binding properties of fatty acid-binding proteins from human, pig, and rat heart.

  1988cited by this paper
• Isolation and characterization of fatty acid binding proteins from mammary tissue of lactating rats.

  1988cited by this paper
• Fatty acid-binding protein, a potential regulator of energy production in the heart. Investigation of mechanisms by electron spin resonance.

  1988cited by this paper
• Thermodynamics of protein-ligand interactions: calorimetric approaches.

  1983cited by this paper
• Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.

  1983cited by this paper
• Heat capacity and entropy changes in processes involving proteins.

  1977cited by this paper
• Some micellar properties of long-chain acylcarnitines.

  1970cited by this paper
• Electrometric determination of critical micelle concentration of soap solutions

  1967cited by this paper

• Insulin Resistance and Inflammation

  2026cites this paper
• EPA and DHA acylcarnitines are less cardiotoxic than are saturated and monounsaturated long‐chain acylcarnitines

  2025cites this paper
• Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure

  2025cites this paper
• Fatty acid binding proteins-mediated mitochondrial dysfunction in the development of age-related diseases: A review.

  2025cites this paper
• Identification and Functional Validation of ACSL1 and FABP3 as Muscle-Related Genes Screened by Transcriptomics in Crossbred Duroc × Berkshire × Diannan Small-Eared Pigs

  2025cites this paper
• LC–MS/MS-based simultaneous quantification of acylcarnitines, eicosapentaenoic acid, and docosahexaenoic acid: exploring potential biomarkers in human plasma

  2025influential citation
• Association Between FABP3 and FABP4 Genes with Changes in Milk Composition and Fatty Acid Profiles in the Native Southern Yellow Cattle Breed

  2025cites this paper
• A versatile delivery vehicle for cellular oxygen and fuels or metabolic sensor? A review and perspective on the functions of myoglobin

  2024cites this paper
• Endothelial dysfunction: mechanisms and contribution to diseases

  2024cites this paper
• Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program.

  2024cites this paper
• Fatty acid β-oxidation in brain mitochondria: Insights from high-resolution respirometry in mouse, rat and Drosophila brain, ischemia and aging models.

  2024cites this paper
• Diāna Zeļencova-Gopejenko STRUCTURAL AND FUNCTIONAL STUDIES OF PROTEINS INVOLVED IN THE REGULATION OF FATTY ACID METABOLISM

  2023influential citation