FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway.
FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway.
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DOI：
10.3389/fcvm.2021.722908
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发表时间：
2021
影响因子：
3.6
通讯作者：
Chen K
中科院分区：
文献类型：
--
作者：
Zhuang L;Mao Y;Liu Z;Li C;Jin Q;Lu L;Tao R;Yan X;Chen K
背景资料：心脏肥大伴随着多种心血管疾病（CVD），由于CVD在全球的高发病率和死亡率，对心肌肥大的发病机制的研究变得越来越重要。我们的目的是确定脂肪酸结合蛋白3（FABP 3）在横主动脉缩窄（TAC）诱导的心肌肥厚中的代谢作用。方法和结果：横向主动脉缩窄或血管紧张素II治疗显着上调Fabp 3的表达。值得注意的是，Fabp 3消融加重了TAC诱导的心脏肥大和心功能不全。多组学分析显示，Fabp 3缺陷的心脏表现出破坏的代谢特征，其特征在于糖酵解增加，毒性脂质积累，以及在肥大刺激下受损的脂肪酸氧化和ATP产生。在机制上，FABP 3通过直接与PPARα相互作用介导代谢重编程，从而阻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Fabp 3缺乏的促肥大作用。结论：这些发现揭示了FABP 3-PPARα轴在代谢稳态和肥大发展中不可或缺的作用，为肥大的治疗提供了新的思路。
Background: 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. Methods and Results: 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. Conclusions: 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.