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.

脂滴 （LD） 为三酰基甘油储存提供了储存库，是细胞中脂肪酸运输和信号转导的中心枢纽。脂肪分解通过未知机制通过 SIRT1/PGC-1α/PPARα 依赖性途径促进线粒体生物发生和氧化代谢。在此，我们确定单不饱和脂肪酸 （MUFA） 变构激活 SIRT1 以对抗选定的肽底物，例如 PGC-1α。MUFA 以 SIRT1 依赖性方式增强 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，我们将已知可增强线粒体生物发生和功能的 LD 蛋白 perilipin 5 （PLIN5） 表征为一种脂肪酸结合蛋白，它优先结合 LD 衍生的单不饱和脂肪酸并在 cAMP/PKA 介导的脂肪分解刺激后将它们运输到细胞核。因此，这些研究确定了 SIRT1 的第一个已知的内源性变构调节剂，并表征了 LD 核信号轴，该轴是 MUFA 和 PLIN5 已知代谢益处的基础。