Kim Joon T, Jedrychowski Mark P, Wei Wei, Fernandez Daniel, Fischer Curt R, Banik Steven M, Spiegelman Bruce M, Long Jonathan Z
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Cell Chem Biol. 2020 Sep 17;27(9):1130-1139.e4. doi: 10.1016/j.chembiol.2020.04.009. Epub 2020 May 12.
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-酰基氨基酸是一类可刺激产热的冷诱导循环脂质。它们的生物合成由一种名为PM20D1的分泌酶介导。在血浆复杂环境中调节PM20D1或N-酰基氨基酸活性的细胞外机制尚不清楚。利用定量蛋白质组学，我们在此表明PM20D1与低密度和高密度脂蛋白紧密结合循环。脂蛋白颗粒在体外是PM20D1活性以及在体内是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，它在空间上使N-酰基氨基酸与其产生部位分离，赋予其抗水解降解能力，并在产热的“游离”部分与无活性的“结合”部分之间建立平衡。这些数据将脂蛋白颗粒确立为N-酰基氨基酸生物合成的主要细胞外场所，并确定了一个调节循环产热脂质家族活性的脂蛋白-白蛋白网络。
