BCAA mediated microbiota-liver-heart crosstalk regulates diabetic cardiomyopathy via FGF21.

IF 13.8 1区生物学 Q1 MICROBIOLOGY

Microbiome Pub Date : 2024-08-24 DOI:10.1186/s40168-024-01872-3

Hong Zheng, Xi Zhang, Chen Li, Die Wang, Yuying Shen, Jiahui Lu, Liangcai Zhao, Xiaokun Li, Hongchang Gao

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引用次数: 0

Abstract

Background: Diabetic cardiomyopathy (DCM) is one of leading causes of diabetes-associated mortality. The gut microbiota-derived branched-chain amino acids (BCAA) have been reported to play a central role in the onset and progression of DCM, but the potential mechanisms remain elusive.

Results: We found the type 1 diabetes (T1D) mice had higher circulating BCAA levels due to a reduced BCAA degradation ability of the gut microbiota. Excess BCAA decreased hepatic FGF21 production by inhibiting PPARα signaling pathway and thereby resulted in a higher expression level of cardiac LAT1 via transcription factor Zbtb7c. High cardiac LAT1 increased the levels of BCAA in the heart and then caused mitochondrial damage and myocardial apoptosis through mTOR signaling pathway, leading to cardiac fibrosis and dysfunction in T1D mice. Additionally, transplant of faecal microbiota from healthy mice alleviated cardiac dysfunction in T1D mice, but this effect was abolished by FGF21 knockdown.

Conclusions: Our study sheds light on BCAA-mediated crosstalk among the gut microbiota, liver and heart to promote DCM and FGF21 serves as a key mediator. Video Abstract.

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BCAA 介导的微生物群-肝脏-心脏串扰通过 FGF21 调节糖尿病心肌病。

背景：糖尿病心肌病（DCM）是糖尿病相关死亡的主要原因之一。据报道，肠道微生物群衍生的支链氨基酸（BCAA）在糖尿病心肌病的发病和进展中起着核心作用，但其潜在机制仍难以捉摸：我们发现，由于肠道微生物群的 BCAA 降解能力降低，1 型糖尿病（T1D）小鼠的循环 BCAA 水平较高。过量的 BCAA 通过抑制 PPARα 信号通路减少了肝脏 FGF21 的产生，从而通过转录因子 Zbtb7c 导致心脏 LAT1 表达水平升高。高水平的心脏LAT1会增加心脏中的BCAA水平，然后通过mTOR信号通路引起线粒体损伤和心肌凋亡，导致T1D小鼠心脏纤维化和功能障碍。此外，移植健康小鼠的粪便微生物群可缓解T1D小鼠的心脏功能障碍，但这种效应因FGF21基因敲除而消失：我们的研究揭示了BCAA介导的肠道微生物群、肝脏和心脏之间的串联促进了DCM，而FGF21是一个关键的介质。视频摘要

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Microbiome MICROBIOLOGY-

CiteScore

21.90

自引率

2.60%

发文量

198

审稿时长

4 weeks

期刊介绍： Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.