脂肪酸通过促进线粒体自噬改善心衰的机制及应用

Heart failure is characterized by reduced fatty acids (FA) utilization associated with mitochondrial dysfunction. Recent studies have shown that enhancing FA utilization through treatment with high fat diet exerts cardioprotection against heart failure. We recently found that FA exerts cardioprotection through improvement of mitochondrial quality in the failing heart. Heart failure was associated with mitochondrial dysfunction which was resulted from a decrease of cardiac FA utilization. However, mitophagy, a process for clearance of damaged mitochondria, was suppressed. Enhancing FA utilization improved mitochondrial quality and promoted mitophagy. In addition, FA increased mitophagy and ULK1 translocation into mitochondria in a dose-dependent manner in vitro. These results suggested that FA may protect the failing heart through ULK1-mediated mitophagy. Thus, our aim is to investigate the effects of FA on cardiac mitophagy and its underlying mechanisms and application in cardioprotection against heart failure. This study was designed to 1) examine the effects of different types of FA (including ketone body) and its metabolic products on cardiac mitophagy; 2) explore the underlying mechanisms of the regulation of mitophagy by FA; 3) examine the role of this regulation in the development of heart failure and search for new strategy for intervention of heart failure through diet. This study will elucidate a novel role of FA in the regulation of mitochondrial quality and its role in the development of heart failure, providing new clues for the intervention of heart failure through diet.

心衰发生发展过程中心肌对脂肪酸的利用降低并伴有线粒体损伤，新近发现通过膳食（高脂饮食）增加心肌对脂肪酸的利用对心衰具有改善作用。我们研究发现脂肪酸发挥心肌保护作用的机制与其改善线粒体质量有关。心衰时心肌对脂肪酸的利用降低致线粒体损伤，但损伤线粒体的清除（线粒体自噬）被抑制；增加心肌脂摄入显著改善线粒体质量，并促进线粒体自噬；离体实验结果表明脂肪酸能够促进ULK1向线粒体转位并增加线粒体自噬：提示脂肪酸可能通过ULK1促进线粒体自噬发挥心衰改善作用。本研究拟阐明脂肪酸促进心肌线粒体自噬的机制及其在心衰发生发展中的作用和在心衰防治中的应用：明确不同脂肪酸（包含酮体）及其代谢产物对心肌线粒体自噬的影响；阐明脂肪酸调控线粒体自噬的分子机制；明确脂肪酸调控线粒体自噬在心衰发生发展中的作用及探讨如何通过膳食干预心肌脂代谢改善心衰。本研究有望揭示脂肪酸改善心衰的机制，为从膳食角度防治心衰提供新线索。

心衰发生发展过程中心肌对脂肪酸的利用降低并伴有线粒体损伤，我们前期研究发现高脂饮食通过增加心肌对脂肪酸的利用对心衰具有保护作用，其机制可能与脂肪酸代谢调控线粒体自噬有关。本课题旨在阐明脂肪酸代谢调控线粒体自噬的机制及如何通过干预心肌脂肪酸代谢防治心衰。主要进展包括：①发现心肌中脂肪酸代谢促进线粒体自噬并改善线粒体功能，其机制为脂肪酸代谢增加心肌细胞Parkin的表达，该过程是高脂饮食保护心衰的机制之一。然而，我们发现长期的高脂饮食喂养并不能增加心衰时心肌对脂肪酸的利用，反而加重心衰的发生发展，提示长期的高脂饮食并不是一种有效地促进心衰时心肌脂肪酸代谢的膳食策略。②发现时间限制性进食（TRF）是一种安全有效的促进心衰时心肌脂肪酸代谢的膳食方案，TRF促进心肌脂肪酸代谢的机制是其增加循环氨基酸水平并促进心肌尿素循环，心肌尿素循环产生的NO能有效改善心肌脂肪酸代谢。③发现运动可有效改善心血管脂肪酸代谢和氨基酸代谢，该效应是其裨益心血管健康的机制之一。运动可增强心血管对脂肪酸的利用，继而改善线粒体功能和促进血管新生。这些研究进展表明脂肪酸不仅是心血管系统的重要代谢底物，也可通过线粒体自噬调控线粒体功能。长期高脂饮食并不是一种高效安全的改善心衰时心肌脂肪酸代谢的膳食策略，而TRF和运动等健康生活方式可有效改善病理条件下心血管对脂肪酸的利用，是防治心血管疾病的更佳策略。