Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations
Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations
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DOI：
10.1172/jci.insight.134340
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发表时间：
2021-05-10
期刊：
影响因子：
8
通讯作者：
Finck, Brian N.
中科院分区：
文献类型：
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作者：
Chambers, Kari T.;Cooper, Michael A.;Finck, Brian N.
Lipin 1 是一种双功能蛋白，是一种转录调节因子，具有磷脂酸 (PA) 磷酸水解酶活性，可将 PA 去磷酸化生成二酰基甘油。人类脂质1突变会导致阵发性横纹肌溶解症，一些受影响的患者表现出心脏异常，包括运动引起的心功能障碍和心脏甘油三酯积聚。此外，心脏衰竭时脂质 1 表达失活，但心肌中脂质 1 失活的影响尚不完全清楚。我们培育了心脏特异性脂质 1 KO (cs-Lpin1(-/-)) 小鼠，以检查脂质 1 在心肌中的内在作用。 Cs-Lpin1(-/-)小鼠具有正常的心脏收缩功能，但心脏轻度肥厚。与同窝对照小鼠相比，cs-Lpin1(-/-)心脏中的PA含量更高，甘油二酯和甘油三酯的含量也出乎意料地增加。当以丙酮酸或琥珀酸作为代谢底物时，Cs-Lpin1(-/-) 小鼠表现出心脏心磷脂含量减少和线粒体呼吸速率受损。主动脉横缩引起的压力超负荷后，脂质1的损失并没有加剧心脏肥大或功能障碍。然而，脂质 1 的缺失会抑制心脏对多巴酚丁胺的离子型反应以及与蛋白激酶 A 信号传导减少相关的运动耐力。这些数据表明，脂质 1 的缺失会损害心脏功能储备，可能是由于对甘油脂稳态、线粒体功能和蛋白激酶 A 信号传导的影响。
Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1(-/-)) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1(-/-) mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1(-/-) hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1(-/-) mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling.