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

Abstract

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 ␣-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 ϩ 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. Key Words: lipids Ⅲ metabolism Ⅲ cardiomyopathy C ardiomyopathy has been observed in a variety of metabolic disorders. In inherited disorders of ␤-oxidation, accumulation of unmetabolized lipid in cardiac myocytes is associated with ventricular systolic dysfunction. 1 In obesity, increased myocardial oxygen consumption and decreased efficiency may contribute to diastolic and systolic dysfunction. 2,3 In diabetes mellitus, heart failure in the absence of valvular or congenital heart disease, alcoholism, hypertension, or significant epicardial coronary atherosclerosis is defined as diabetic cardiomyopathy and accounts for significant morbidity and mortality in people with type 1 and type 2 diabetes. 4 Echocardiographic and hemodynamic studies suggest left ventricular (LV) diastolic impairment represents an early preclinical manifestation of diabetic cardiomyopathy that may progress over an extended period of time to both diastolic and systolic dysfunction. 5,6 In these metabolic disorders, systemic metabolic perturbations lead to myocyte dysfunction and/or loss. Glucotoxicity, 7 ATP depletion, 8 and maladaptive changes in metabolic substrate utilization 9 are mechanisms proposed to contribute to cardiac dysfunction. It has also been hypothesized that mismatch between tissue free fatty acid (FFA) import and utilization leads to lipid accumulation and results in lipotoxicity. In diabetes, this imbalance results from high-serum F...

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

“…Stable HEK-293 cell lines over-expressing murine FATP1 demonstrate increased LCFA uptake and triacylglycerol accumulation (12). A transgenic mouse model with cardiac-specific expression of FATP1 demonstrated increased myocardial LCFA uptake (13). Disruption of the FATP1 homolog expressed in yeast, fat1p, markedly impaired LCFA uptake (14), and a murine FATP1 knockout mouse exhibited reduced muscle acyl-CoA levels and increased insulin sensitivity (15).…”

Left Ventricular Hypertrophy

“…In addition, the meanϮSEM E/A wave ratio was significantly (PϽ0.05) larger in TAC animals (supplemental Table II), consistent with diastolic dysfunction. 13 Fractional shortening, however, was similar (supplemental Table II), and there was no evidence of altered systolic function or heart failure in TAC animals.…”

“…Seven days after surgery, echocardiographic images were acquired and analyzed using described methods. 12,13 …”

Cardiovascular consequences of obesity and targets for treatment

“…Animal studies suggest that alterations in myocardial metabolism contribute to cardiac dysfunction in obesity [23,55]. Normally, the myocardium is an omnivore, able to utilize multiple substrates for metabolism but in the postnatal, resting, fasted state it primarily uses FAs.…”

“…Studies in animal models show that lipotoxicity may occur via ceramide-dependent or -independent pathways [23,24]. In these animal models of lipotoxicity, the myocardial metabolic abnormalities precede cardiac dysfunction and are thought to contribute to it [23,55,57]. Whether this process also occurs in humans is the subject of intense investigation.…”