Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago (J.R.G., E.D.L.).
Department of Internal Medicine, College of Medicine, The Ohio State University (A.N.C., M.F., E.D.L.), Columbus.
Circulation. 2019 Jun 11;139(24):2765-2777. doi: 10.1161/CIRCULATIONAHA.119.039610. Epub 2019 Mar 26.
Metabolic remodeling in heart failure contributes to dysfunctional lipid trafficking and lipotoxicity. Acyl coenzyme A synthetase-1 (ACSL1) facilitates long-chain fatty acid (LCFA) uptake and activation with coenzyme A (CoA), mediating the fate of LCFA. The authors tested whether cardiac ACSL1 overexpression aids LCFA oxidation and reduces lipotoxicity under pathological stress of transverse aortic constriction (TAC).
Mice with cardiac restricted ACSL1 overexpression (MHC-ACSL1) underwent TAC or sham surgery followed by serial in vivo echocardiography for 14 weeks. At the decompensated stage of hypertrophy, isolated hearts were perfused with C LCFA during dynamic-mode C nuclear magnetic resonance followed by in vitro nuclear magnetic resonance and mass spectrometry analysis to assess intramyocardial lipid trafficking. In parallel, acyl CoA was measured in tissue obtained from heart failure patients pre- and postleft ventricular device implantation plus matched controls.
TAC-induced cardiac hypertrophy and dysfunction was mitigated in MHC-ACSL1 hearts compared with nontransgenic hearts. At 14 weeks, TAC increased heart weight to tibia length by 46% in nontransgenic mice, but only 26% in MHC-ACSL1 mice, whereas ACSL1 mice retained greater ejection fraction (ACSL1 TAC: 65.8±7.5%; nontransgenic TAC: 45.9±7.3) and improvement in diastolic E/E'. Functional improvements were mediated by ACSL1 changes to cardiac LCFA trafficking. ACSL1 accelerated LCFA uptake, preventing C16 acyl CoA loss post-TAC. Long-chain acyl CoA was similarly reduced in human failing myocardium and restored to control levels by mechanical unloading. ACSL1 trafficked LCFA into ceramides without normalizing the reduced triglyceride storage in TAC. ACSL1 prevented de novo synthesis of cardiotoxic C16- and C24-, and C24:1 ceramides and increased potentially cardioprotective C20- and C22-ceramides post-TAC. ACLS1 overexpression activated AMP activated protein kinase at baseline, but during TAC, prevented the reduced LCFA oxidation in hypertrophic hearts and normalized energy state (phosphocreatine:ATP) and consequently, AMP activated protein kinase activation.
This is the first demonstration of reduced acyl CoA in failing hearts of humans and mice, and suggests possible mechanisms for maintaining mitochondrial oxidative energy metabolism by restoring long-chain acyl CoA through ASCL1 activation and mechanical unloading. By mitigating cardiac lipotoxicity, via redirected LCFA trafficking to ceramides, and restoring acyl CoA, ACSL1 delayed progressive cardiac remodeling and failure.
心力衰竭中的代谢重塑导致功能失调的脂质转运和脂肪毒性。酰基辅酶 A 合成酶-1（ACSL1）通过辅酶 A（CoA）促进长链脂肪酸（LCFA）的摄取和激活，介导 LCFA 的命运。作者测试了心脏 ACSL1 过表达是否有助于在横主动脉缩窄（TAC）的病理应激下促进 LCFA 氧化并减少脂肪毒性。
在心脏限制 ACSL1 过表达（MHC-ACSL1）的小鼠中进行 TAC 或假手术，然后进行 14 周的连续体内超声心动图检查。在肥厚的失代偿阶段，用 C 长链脂肪酸在动态模式 C 磁共振下对分离的心脏进行灌注，然后进行体外磁共振和质谱分析，以评估心肌内脂质转运。平行地，在左心室装置植入前后测量心力衰竭患者组织中的酰基辅酶 A，并与匹配的对照进行比较。
与非转基因心脏相比，TAC 诱导的心脏肥大和功能障碍在 MHC-ACSL1 心脏中得到缓解。在 14 周时，TAC 使非转基因小鼠的心脏重量与胫骨长度的比值增加了 46%，但在 MHC-ACSL1 小鼠中仅增加了 26%，而 ACSL1 小鼠保留了更高的射血分数（ACSL1 TAC：65.8±7.5%；非转基因 TAC：45.9±7.3%）和舒张 E/E'的改善。功能改善是由 ACSL1 对心脏 LCFA 转运的改变介导的。ACSL1 加速了 LCFA 的摄取，防止 TAC 后 C16 酰基辅酶 A 的损失。长链酰基辅酶 A在人类衰竭的心肌中也同样减少，并通过机械卸载恢复到对照水平。ACSL1 将 LCFA 转运到神经酰胺中，但没有使 TAC 中减少的甘油三酯储存正常化。ACSL1 可防止新合成的心脏毒性 C16-和 C24-和 C24：1 神经酰胺的合成，并在 TAC 后增加潜在的心脏保护 C20-和 C22-神经酰胺。ACSL1 在基线时激活 AMP 激活的蛋白激酶，但在 TAC 期间，防止了肥厚心脏中 LCFA 氧化的减少，并使能量状态（磷酸肌酸：ATP）正常化，从而激活 AMP 激活的蛋白激酶。
这是首次在人类和小鼠衰竭的心脏中发现减少的酰基辅酶 A 的证明，并提出了通过激活 ACSL1 和机械卸载来恢复长链酰基辅酶 A，从而维持线粒体氧化能量代谢的可能机制。通过将 LCFA 转运到神经酰胺，以及恢复酰基辅酶 A，ACSL1 减轻了心脏脂肪毒性，从而延缓了进行性心脏重塑和衰竭。
