小柯机器人

西班牙国家心血管疾病研究中心Mercedes Ricote团队发现，母体乳汁中的γ-亚麻酸驱动心脏代谢的成熟。相关论文于2023年5月24日在线发表在《自然》杂志上。

研究人员表明，这一转变是由母体提供的γ-亚麻酸（GLA）协调的，这是一种富含在母体乳汁中的18:3欧米茄-6脂肪酸。GLA结合并激活视黄醇X受体4（RXR），这些配体调节的转录因子从胚胎阶段就在心肌细胞中表达。多方面的全基因组分析显示，在胚胎心肌细胞中缺乏RXR会导致异常的染色质景观，阻止诱导控制线粒体脂肪酸稳态的RXR依赖性基因表达特征。随之而来的有缺陷的代谢转变的特点是线粒体脂质的能量生产减弱和葡萄糖消耗增加，导致围产期心脏功能障碍和死亡。最后，在体外和体内实验中，GLA补充剂诱导了RXR依赖性的心肌细胞线粒体脂肪酸平衡特征的表达。因此，这项研究确定了GLA-RXR轴是母体控制围产期心脏代谢的关键转录调节机制。

据介绍，出生给心肌细胞带来了新陈代谢的挑战，因为它们为产后的能量生产重新塑造了从葡萄糖到脂肪酸的能源偏好。这种适应部分是由产后环境变化引发的，但协调心肌细胞成熟的分子仍然是未知的。

附：英文原文

Title: γ-Linolenic acid in maternal milk drives cardiac metabolic maturation

Author: Paredes, Ana, Justo-Mndez, Raquel, Jimnez-Blasco, Daniel, Nez, Vanessa, Calero, Irene, Villalba-Orero, Mara, Alegre-Mart, Andrea, Fischer, Thierry, Gradillas, Ana, SantAnna, Viviane Aparecida Rodrigues, Were, Felipe, Huang, Zhiqiang, Hernansanz-Agustn, Pablo, Contreras, Carmen, Martnez, Fernando, Camafeita, Emilio, Vzquez, Jess, Ruiz-Cabello, Jess, Area-Gmez, Estela, Snchez-Cabo, Ftima, Treuter, Eckardt, Bolaos, Juan Pedro, Estbanez-Perpi, Eva, Ruprez, Francisco Javier, Barbas, Coral, Enrquez, Jos Antonio, Ricote, Mercedes

Issue&Volume: 2023-05-24

Abstract: Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production1,2. This adaptation is triggered in part by post-partum environmental changes3, but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA–RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism.

DOI: 10.1038/s41586-023-06068-7

Source: https://www.nature.com/articles/s41586-023-06068-7

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