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

Abstract

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.

Structural and Functional Studies of Proteins Involved in the Regulation of Fatty Acid Metabolism

“…Similarly, the cytotoxic effects of palmitoyl carnitine were effectively diminished with overexpression of FABP3 in PANC-1 cells. These data were obtained in collaboration with the Laboratory of Pharmaceutical Pharmacology (LIOS) and were described in the author's publication [38]. Thus, it was hypothesized that FABP3 is capable of binding not only FAs but also FA carnitine esters thereby protecting the cells from their high toxicity.…”

“…The obtained data confirm that the used additives neither affect the FABP3 structure nor interfere with FA binding nor alter the conformation of the FABP3-FA complex. The obtained data were described in the author's publication [38].…”

“…On the other hand, the restricted flexibility positively affected the protein-ligand non-covalent interactions. The obtained data were described in the author's publication [38].…”

“…These data indicate that a novel binding mechanism for monounsaturated acylcarnitines was observed. The obtained data were described in the author's publication [38].…”

“…Most probably, this occurs as the ligand is in the ester form now and L-carnitine cannot enter the hydrophobic binding site and make contact with its carboxyl group. The obtained data were described in the author's publication [38].…”