Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Babak Razani,Haixia Zhang,P Christian Schulze,Joel D Schilling,John Verbsky,Irfan J Lodhi,Veli K Topkara,Chu Feng,Trey Coleman,Attila Kovacs,Daniel P Kelly,Jeffrey E Saffitz,Gerald W Dorn,Colin G Nichols,Clay F Semenkovich

doi:10.1074/jbc.m111.230508

Abstract

Fatty acid synthase (FAS) promotes energy storage through de novo lipogenesis and participates in signaling by the nuclear receptor PPARα 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 PPARα 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 ∼1 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.

Highlights

Storing energy preserves the function of many mammalian tissues during physiological and pathological stress
Mice carrying the floxed Fatty acid synthase (FAS) gene were crossed with transgenic mice expressing Cre driven by the ␣-myosin heavy chain promoter to yield FAS knockout in the myocardium (FASKard) progeny (Fig. 1D) that were born at the expected Mendelian frequency and developed normally
Adult cardiac myocytes derived from FASKard hearts had a significantly lower capacity to synthesize palmitate, the principal fatty acid synthesized by FAS, than control myocytes (Fig. 1H)

Summary

Introduction

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 FAS2 [2, 3]. Elegant studies dating from a half century ago of myocardial fatty acid oxidation [12,13,14], lipid pools [14, 15], and lipid synthesis [14] demonstrated that the myocardium derives most of its fat from the circulation In view of these findings and the notion that the heart has little need to store energy, de novo lipogenesis in myocardial physiology and pathophysiology has been largely forgotten. We found that myocardial FAS regulates calcium signals and adaptation to stress

Methods

Results

Conclusion