Zhuang Lingfang, Mao Ye, Liu Zizhu, Li Chenni, Jin Qi, Lu Lin, Tao Rong, Yan Xiaoxiang, Chen Kang
Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Cardiovasc Med. 2021 Aug 12;8:722908. doi: 10.3389/fcvm.2021.722908. eCollection 2021.
Cardiac hypertrophy was accompanied by various cardiovascular diseases (CVDs), and due to the high global incidence and mortality of CVDs, it has become increasingly critical to characterize the pathogenesis of cardiac hypertrophy. We aimed to determine the metabolic roles of fatty acid binding protein 3 (FABP3) on transverse aortic constriction (TAC)-induced cardiac hypertrophy. Transverse aortic constriction or Ang II treatment markedly upregulated Fabp3 expression. Notably, Fabp3 ablation aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction. Multi-omics analysis revealed that Fabp3-deficient hearts exhibited disrupted metabolic signatures characterized by increased glycolysis, toxic lipid accumulation, and compromised fatty acid oxidation and ATP production under hypertrophic stimuli. Mechanistically, FABP3 mediated metabolic reprogramming by directly interacting with PPARα, which prevented its degradation and synergistically modulated its transcriptional activity on Mlycd and Gck. Finally, treatment with the PPARα agonist, fenofibrate, rescued the pro-hypertrophic effects of Fabp3 deficiency. Collectively, these findings reveal the indispensable roles of the FABP3-PPARα axis on metabolic homeostasis and the development of hypertrophy, which sheds new light on the treatment of hypertrophy.
心脏肥大与多种心血管疾病（CVDs）相关，由于CVDs在全球的高发病率和死亡率，阐明心脏肥大的发病机制变得越来越关键。我们旨在确定脂肪酸结合蛋白3（FABP3）在横主动脉缩窄（TAC）诱导的心脏肥大中的代谢作用。横主动脉缩窄或Ang II处理显著上调Fabp3表达。值得注意的是，Fabp3基因敲除加剧了TAC诱导的心脏肥大和心脏功能障碍。多组学分析显示，在肥厚刺激下，Fabp3基因缺陷的心脏表现出代谢特征紊乱，其特点是糖酵解增加、有毒脂质积累以及脂肪酸氧化和ATP生成受损。机制上，FABP3通过直接与PPARα相互作用介导代谢重编程，从而防止其降解并协同调节其对Mlycd和Gck的转录活性。最后，用PPARα激动剂非诺贝特治疗挽救了Fabp3基因缺陷的促肥大作用。总的来说，这些发现揭示了FABP3-PPARα轴在代谢稳态和肥大发展中的不可或缺的作用，为肥大的治疗提供了新的思路。
