GCN5L1 损害小鼠的舒张功能通过限制心脏丙酮酸氧化的高脂肪饮食

GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation.

Keywords：Acetylation, Diastolic dysfunction, Heart failure, Mitochondria, Pyruvate dehydrogenase 

关键词：乙酰化、舒张功能障碍、心力衰竭、线粒体、丙酮酸脱氢酶

哺乳动物：小鼠

组织：心脏
作者：Thapa Dharendra, Bugga Paramesha, Mushala Bellina AS, Manning Janet R, Stoner Michael W, McMahon Brenda, Zeng Xuemei, Cantrell Pamela S, Yates Nathan, Xie Bingxian, Edmunds Lia R, Jurczak Michael J, Scott Iain

出版期刊：《Physiol Rep》（2022）

Abstract：

Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear. In this report, we use a diet-induced obesity model in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits that may contribute to the development of diastolic dysfunction in mouse hearts. Cardiomyocyte-specific deletion of the mitochondrial lysine acetylation regulatory protein GCN5L1 prevented hyperacetylation of the PDH complex subunit PDHA1, allowing aged obese mice to continue using pyruvate as a bioenergetic substrate in the heart. Our findings suggest that changes in mitochondrial protein lysine acetylation represent a key metabolic component of diastolic dysfunction that precedes the development of heart failure.

文章摘要：

左心室舒张功能障碍是一种结构和功能状况，发生在射血分数保留的心力衰竭 (HFpEF) 之前。舒张功能障碍的病因包括燃料底物代谢的改变，这些改变会对心脏生物能量学产生负面影响，并可能促使最终转变为心力衰竭。迄今为止，调节燃料代谢早期变化导致舒张功能障碍的分子机制仍不清楚。在本报告中，我们在老年小鼠中使用饮食诱导的肥胖模型来表明丙酮酸脱氢酶 (PDH) 复合物的抑制性赖氨酸乙酰化促进了能量不足，这可能导致小鼠心脏舒张功能障碍的发展。线粒体赖氨酸乙酰化调节蛋白 GCN5L1 的心肌细胞特异性缺失阻止了 PDH 复合物亚基 PDHA1 的过度乙酰化，从而使老年肥胖小鼠能够继续使用丙酮酸作为心脏中的生物能量底物。我们的研究结果表明，线粒体蛋白赖氨酸乙酰化的变化代表了心力衰竭发展之前舒张功能障碍的关键代谢成分。

点击链接即可查看和下载文章：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350469/pdf/PHY2-10-e15415.pdf

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