N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic “free” versus inactive “bound” fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family.

N-酰基氨基酸是一类冷诱导循环脂质，可刺激生热作用。它们的生物合成是由一种称为 PM20D1 的分泌酶介导的。在复杂的血浆环境中调节 PM20D1 或 N-酰基氨基酸活性的细胞外机制仍不清楚。通过定量蛋白质组学，我们发现 PM20D1 的循环与低密度脂蛋白和高密度脂蛋白密切相关。脂蛋白颗粒是体外PM20D1 活性和体内N-酰基氨基酸生物合成的强大共激活剂。我们还确定血清白蛋白是一种生理性 N-酰基氨基酸载体，它在空间上将 N-酰基氨基酸与其生产位点隔离，赋予对水解降解的抵抗力，并在产热“游离”与无活性“结合”之间建立平衡分数。这些数据将脂蛋白颗粒确定为 N-酰基氨基酸生物合成的主要细胞外位点，并确定了调节循环生热脂质家族活性的脂蛋白-白蛋白网络。