title: 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 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.
authors.affiliation: Divisions of Endocrinology, Metabolism, and Lipid Research, Washington University, St. Louis, Missouri 63110; Cardiology, Washington University, St. Louis, Missouri 63110.
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.affiliation: Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Columbia University, New York, New York 10032.
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.affiliation: Cardiology, Washington University, St. Louis, Missouri 63110.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Schilling
authors.affiliation: Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110.
authors.forename: John
authors.initials: J
authors.lastname: Verbsky
authors.affiliation: Divisions of Endocrinology, Metabolism, and Lipid Research, Washington University, St. Louis, Missouri 63110.
authors.forename: Irfan J
authors.initials: IJ
authors.lastname: Lodhi
authors.affiliation: Cardiology, Washington University, St. Louis, Missouri 63110.
authors.forename: Veli K
authors.initials: VK
authors.lastname: Topkara
authors.affiliation: Divisions of Endocrinology, Metabolism, and Lipid Research, Washington University, St. Louis, Missouri 63110.
authors.forename: Chu
authors.initials: C
authors.lastname: Feng
authors.affiliation: Divisions of Endocrinology, Metabolism, and Lipid Research, Washington University, St. Louis, Missouri 63110.
authors.forename: Trey
authors.initials: T
authors.lastname: Coleman
authors.affiliation: Cardiology, Washington University, St. Louis, Missouri 63110.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Sanford-Burnham Medical Research Institute, Orlando, Florida 32827.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.affiliation: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.affiliation: Center for Pharmacogenomics, Washington University, St. Louis, Missouri 63110.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.affiliation: Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: Divisions of Endocrinology, Metabolism, and Lipid Research, Washington University, St. Louis, Missouri 63110; Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110. Electronic address: csemenko@wustl.edu.
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003433:Crosses, Genetic; D004452:Echocardiography / Q000379:methods; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005260:Female; D005838:Genotype; D050155:Lipogenesis; D008297:Male; D051379:Mice; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D064429:Fatty Acid Synthases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2