Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Abstract

Fatty acid synthase (FAS) promotes energy storage through de novo lipogenesis and participates in signaling by the nuclear receptor PPAR␣ in noncardiac tissues. To determine if de novo lipogenesis is relevant to cardiac physiology, we generated and characterized FAS knockout in the myocardium (FASKard) mice. FASKard mice develop normally, manifest normal resting heart function, and have normal cardiac PPAR␣ signaling as well as fatty acid oxidation. However, they decompensate with stress. Most die within 1 h of transverse aortic constriction, probably due to arrhythmia. Voltage clamp measurements of FASKard cardiomyocytes show hyperactivation of L-type calcium channel current that could not be reversed with palmitate supplementation. Of the classic regulators of this current, Ca 2؉ / calmodulin-dependent protein kinase II (CaMKII) but not protein kinase A signaling is activated in FASKard hearts, and knockdown of FAS in cultured cells activates CaMKII. In addition to being intolerant of the stress of acute pressure, FASKard hearts were also intolerant of the stress of aging, reflected as persistent CaMKII hyperactivation, progression to dilatation, and premature death by ϳ1 year of age. CaMKII signaling appears to be pathogenic in FASKard hearts because inhibition of its signaling in vivo rescues mice from early mortality after transverse aortic constriction. FAS was also increased in two mechanistically distinct mouse models of heart failure and in the hearts of humans with end stage cardiomyopathy. These data implicate a novel relationship between FAS and calcium signaling in the heart and suggest that FAS induction in stressed myocardium represents a compensatory response to protect cardiomyocytes from pathological calcium flux.Storing energy preserves the function of many mammalian tissues during physiological and pathological stress. One of the ways that tissues store energy is through de novo lipogenesis, the synthesis of saturated fatty acids from carbohydrate precursors (1). This process, accomplished by iterative two-carbon additions to a fatty acid chain, is mediated by the multifunctional enzyme FAS 2 (2, 3). Initially relegated to cellular housekeeping, FAS was recently also shown to participate in intracellular signaling. Whole body FAS-deficient embryos die before uterine implantation (4), but liver-specific FAS knock-out mice (5) have decreased expression of fatty acid oxidation genes (classic targets of PPAR␣ signaling) and a phenotype resembling PPAR␣-deficient mice (6). Pharmacological activation of PPAR␣ reverses these features, suggesting that FAS generates an endogenous ligand for PPAR␣, and this FAS-dependent molecule was recently identified as a discrete phosphatidylcholine species (7). FAS also triggers PPAR␣ signaling in the hypothalamus (8) and in macrophages (9), raising the possibility that molecules generated by this enzyme are necessary for activating fatty acid metabolism, even in fatty acid-dependent tissues, such as the heart.Myocardial reliance on fatty acids as an energy source...

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

“…The FASN protein level in Tg-FASN hearts was increased ϳ2.4-fold (Fig. 2, F and G), which is comparable with the upregulated FASN level of failing human hearts (10,11).…”

“…Such an approach is also supported by data obtained for myocardium-specific Fasn deficiency, which have revealed the cardioprotective potential of Fasn (10). Moreover, hearts from patients with heart failure showed an increased expression and protein level of FASN 2 (10,11).…”

“…To reproduce the dysfunctional cardiac substrate use, we generated a novel transgenic model with myocardiumspecific FASN expression. The model imitated the up-regulation of FASN, which occurs in patients with heart failure (10,11). In the context of cardiovascular disease and heart failure, the up-regulation of FASN could be a direct consequence of decreased cardiac output and insufficient oxygen supply because FASN is a hypoxia-induced gene (39).…”

“…However, FASN is an essential enzyme that has indispensable functions in energy homeostasis, membrane biology, and neurogenesis, which preclude long term FASN inhibition in vivo (10,33,34). We therefore searched for an alternative strategy to target the dysfunctional cardiac substrate metabolism.…”

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

“…Myocardial fatty acids can also be derived from de novo lipogenesis [25]. Deletion of fatty acid synthetase in heart of mice results in cardiac 180 decompensation in the setting of aortic constriction or aging [27].…”