Li Shen, Liu Hongbo, Hu Hailong, Ha Eunji, Prasad Praveena, Jenkins Brenita C, Das Ujjalkumar Subhash, Mukherjee Sarmistha, Shishikura Kyosuke, Hu Renming, Rader Daniel J, Pei Liming, Baur Joseph A, Matthews Megan L, FitzGerald Garret A, McReynolds Melanie R, Susztak Katalin
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Penn/CHOP Kidney Innovation Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Cell Metab. 2025 Jan 7;37(1):154-168.e7. doi: 10.1016/j.cmet.2024.10.007. Epub 2024 Nov 18.
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.
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困难。在这里，我们鉴定出了β-内酰胺酶（LACTB），这是一种新基因，其表达受到导致肾功能障碍和高脂血症的基因变异的靶向作用。LACTB基因缺失的小鼠出现糖耐量受损、血脂水平升高以及对肾脏疾病的敏感性增加，而肾小管特异性过表达LACTB的小鼠则受到肾脏损伤的保护。我们发现LACTB是一种新型线粒体蛋白酶，可切割并激活磷脂酶A2第VI组（PLA2G6），而PLA2G6本身就是一种肾脏代谢风险基因。在肾小管特异性LACTB过表达的小鼠中，PLA2G6的基因缺失消除了LACTB的保护功能。通过小鼠和人类脂质组学研究，我们发现LACTB及其下游的PLA2G6可将氧化型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，我们确定了一种针对肾脏代谢紊乱的新基因和一个可靶向的核心途径。
