美国宾夕法尼亚大学Katalin Susztak研究团队发现，人类遗传学揭示心血管-肾脏-代谢综合征中线粒体LACTB介导的脂质代谢的汇聚信号。相关论文于2024年11月18日在线发表在《细胞—代谢》杂志上。

研究人员鉴定了β-内酰胺酶（LACTB），一种新型基因，其表达受到引起肾脏功能障碍和高脂血症的遗传变异的调控。LACTB缺失的小鼠表现出葡萄糖耐受性受损、脂质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的小鼠则能抵抗肾损伤。

研究人员发现，LACTB是一种新型线粒体蛋白酶，能够切割并激活磷脂酶A2第六组（PLA2G6），后者本身就是一个与肾脏-代谢风险相关的基因。在线粒体特异性过表达LACTB的小鼠中，PLA2G6的遗传缺失消除了LACTB的保护作用。

通过小鼠和人类脂质组学研究，研究人员发现LACTB及其下游的PLA2G6，能将氧化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，研究人员识别了一个新基因及其作为肾脏-代谢疾病的核心靶向通路。

据介绍，尽管近期进行了大规模全基因组关联研究，但对心血管-肾脏-代谢综合征的理解仍然困难。

附：英文原文

Title: Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome

Author: Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C. Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J. Rader, Liming Pei, Joseph A. Baur, Megan L. Matthews, Garret A. FitzGerald, Melanie R. McReynolds, Katalin Susztak

Issue&Volume: 2024-11-18

Abstract: 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.

DOI: 10.1016/j.cmet.2024.10.007

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00403-0