Transgenic Expression of Fatty Acid Transport Protein 1 in the Heart Causes Lipotoxic Cardiomyopathy

TLDR

Systemic metabolic disturbances can cause cardiac myocyte dysfunction and heart failure independent of coronary artery disease. The study tests whether disrupting lipid homeostasis in cardiomyocytes leads to cardiac dysfunction. Transgenic mice were created with cardiac‑specific overexpression of FATP1 driven by the α‑myosin heavy chain promoter. Transgenic mice overexpressing FATP1 showed a fourfold increase in myocardial free fatty acid uptake, doubled cardiomyocyte FFA accumulation and metabolism, and by three months displayed diastolic dysfunction with preserved systolic function, biatrial enlargement, prolonged QTc intervals, and reduced ventricular repolarizing K⁺ currents, mirroring diabetic cardiomyopathy and confirming FATP1’s role in cardiac FFA import.

Abstract

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the α-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT c intervals, reflecting reductions in the densities of repolarizing, voltage-gated K + currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.