Lipid droplets (LDs) provide a reservoir for triacylglycerol storage and are a central hub for fatty acid trafficking and signaling in cells. Lipolysis promotes mitochondrial biogenesis and oxidative metabolism via a SIRT1/PGC-1α/PPARα-dependent pathway through an unknown mechanism. Herein, we identify that monounsaturated fatty acids (MUFAs) allosterically activate SIRT1 toward select peptide-substrates such as PGC-1α. MUFAs enhance PGC-1α/PPARα signaling and promote oxidative metabolism in cells and animal models in a SIRT1-dependent manner. Moreover, we characterize the LD protein perilipin 5 (PLIN5), which is known to enhance mitochondrial biogenesis and function, to be a fatty-acid-binding protein that preferentially binds LD-derived monounsaturated fatty acids and traffics them to the nucleus following cAMP/PKA-mediated lipolytic stimulation. Thus, these studies identify the first-known endogenous allosteric modulators of SIRT1 and characterize a LD-nuclear signaling axis that underlies the known metabolic benefits of MUFAs and PLIN5.

脂质小滴（LDs）提供了三酰基甘油的储存库，并且是细胞中脂肪酸运输和信号传导的中心枢纽。脂解通过依赖于未知机制的SIRT1 /PGC-1α/PPARα依赖性途径促进线粒体生物发生和氧化代谢。在本文中，我们确定单不饱和脂肪酸（MUFA）变构激活SIRT1朝向选定的肽底物，如PGC-1α。MUFA以依赖SIRT1的方式增强PGC-1α/PPARα信号传导并促进细胞和动物模型中的氧化代谢。此外，我们将LD蛋白perilipin 5（PLIN5）表征为已知增强线粒体生物发生和功能的脂肪酸结合蛋白，它优先结合LD衍生的单不饱和脂肪酸，并在cAMP /后将其运输至细胞核。 PKA介导的脂解刺激。