Jose Anu, Pakkiriswami Shanmugasundaram, Mercer Angella, Paudel Yadab, Yi Esther, Fernando Jeffy, Pulinilkunnil Thomas, Kienesberger Petra C
Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada.
Am J Physiol Heart Circ Physiol. 2025 Feb 1;328(2):H333-H347. doi: 10.1152/ajpheart.00518.2024. Epub 2025 Jan 13.
Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3 mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3) and LPP3 mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 wk, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3 mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared with LPP3 mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3 mice were protected from increased plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared with LPP3 mice. Female LPP3 mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy. Lipid phosphate phosphatase 3 (LPP3) hydrolyzes bioactive lipids including lysophosphatidic acid (LPA), elevated levels of which are implicated in obesity-induced metabolic and cardiac dysfunction. We show that cardiac-specific overexpression of LPP3 lowers plasma LPA levels, blunts LPA signaling in cardiomyocytes, and increases pyruvate-linked mitochondrial respiration in the heart at baseline in both male and female mice. In female mice, LPP3 overexpression also protects from high-fat diet-induced obesity, insulin resistance, and cardiac dysfunction.
脂质磷酸酶3（LPP3）是一种膜结合酶，可水解包括生物活性脂质溶血磷脂酸（LPA）在内的脂质磷酸。循环中LPA生成增加和细胞内LPA信号传导与肥胖诱导的代谢和心脏功能障碍有关。心肌细胞中LPP3的缺失会增加循环中LPA水平，并导致小鼠心力衰竭和线粒体功能障碍。为了研究心肌细胞中LPP3调节对肥胖诱导的心肌病的影响，我们构建了由α肌球蛋白重链启动子驱动的具有心肌细胞特异性LPP3过表达的小鼠（LPP3小鼠）。雌性和雄性对照（LPP3）小鼠和LPP3小鼠被喂食低脂饮食（LFD）或高脂饮食（HFD）长达22 - 23周，随后分析葡萄糖稳态、心脏功能、血浆LPA水平以及心肌纤维中的线粒体呼吸。在LFD喂养下，与LPP3小鼠相比，雌性和雄性LPP3小鼠的血浆LPA水平均显著降低，丙酮酸相关呼吸增加，而不同基因型之间的体重和整体胰岛素敏感性相似。在HFD喂养后，与LPP3小鼠相比，雌性LPP3小鼠可免受血浆LPA水平升高、肥胖、全身胰岛素抵抗以及收缩期和舒张期心脏功能障碍的影响。雌性LPP3小鼠在HFD喂养后还维持了心肌丙酮酸相关线粒体呼吸的升高，而在HFD喂养的雄性小鼠中，不同基因型之间的线粒体呼吸相似。这项研究表明，心肌细胞特异性LPP3上调尤其能保护雌性小鼠免受HFD诱导的代谢功能障碍和心肌病的影响。脂质磷酸酶3（LPP3）水解包括溶血磷脂酸（LPA）在内的生物活性脂质，其水平升高与肥胖诱导的代谢和心脏功能障碍有关。我们表明，在雄性和雌性小鼠中，心脏特异性LPP3过表达均可降低血浆LPA水平，减弱心肌细胞中的LPA信号传导，并在基线时增加心脏中丙酮酸相关的线粒体呼吸。在雌性小鼠中，LPP3过表达还可预防高脂饮食诱导的肥胖、胰岛素抵抗和心脏功能障碍。
