The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.

中文翻译：

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人类遗传学在心血管-肾脏-代谢综合征中鉴定线粒体 LACTB 介导的脂质代谢中的收敛信号


尽管最近进行了大规模的全基因组关联研究，但对心血管-肾脏-代谢综合征的理解仍然很困难。在这里，我们鉴定了 β-内酰胺酶 （LACTB），这是一种新型基因，其表达受导致肾功能障碍和高脂血症的遗传变异的靶向。LACTB 缺失的小鼠葡萄糖耐量受损，血脂水平升高，对肾脏疾病的敏感性增加，而肾小管特异性过表达 LACTB 的小鼠则免受肾损伤。我们表明 LACTB 是一种新型线粒体蛋白酶裂解并激活磷脂酶 A2 第 VI 组 （PLA2G6），本身就是一种肾脏代谢风险基因。肾小管特异性 LACTB 过表达小鼠中 PLA2G6 的基因缺失消除了 LACTB 的保护功能。通过小鼠和人脂质组学研究，我们表明 LACTB 和下游 PLA2G6 将氧化的磷脂酰乙醇胺转化为溶血磷脂酰乙醇胺，从而调节线粒体功能和铁死亡。总之，我们确定了一种新的基因和肾脏代谢紊乱的核心靶向途径。