High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants (NCT03946774 and NCT03994367) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

高蛋白质摄入量在西方社会很常见，并且经常被宣传为健康生活方式的一部分；然而，巨噬细胞中氨基酸介导的哺乳动物雷帕霉素靶点（mTOR）信号传导与缺血性心血管疾病的发病机制有关。在对男性和女性参与者（NCT03946774 和 NCT03994367）进行的一系列临床研究中，涉及分级蛋白质摄入量以及详细的血浆氨基酸分析和人单核细胞/巨噬细胞实验，我们确定亮氨酸是巨噬细胞中 mTOR 信号传导的关键激活剂。我们描述了高蛋白质摄入和循环亮氨酸对单核细胞/巨噬细胞的阈值效应，其中只有每餐超过 25 g 的蛋白质才会诱导 mTOR 激活和功能效应。通过设计代表一般人群摄入量的蛋白质和亮氨酸含量的特定饮食，我们在小鼠模型中证实了这种阈值效应，并发现摄入超过膳食能量需求 22% 的蛋白质会导致雄性小鼠动脉粥样硬化。这些数据证明了过量饮食蛋白质对心血管风险产生不利影响的机制基础。