Najt Charles P, Khan Salmaan A, Heden Timothy D, Witthuhn Bruce A, Perez Minervo, Heier Jason L, Mead Linnea E, Franklin Mallory P, Karanja Kenneth K, Graham Mark J, Mashek Mara T, Bernlohr David A, Parker Laurie, Chow Lisa S, Mashek Douglas G
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Department of Food Science and Nutrition, University of Minnesota, Minneapolis, MN, USA.
Mol Cell. 2020 Feb 20;77(4):810-824.e8. doi: 10.1016/j.molcel.2019.12.003. Epub 2019 Dec 31.
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（LDs）为三酰甘油的储存提供了一个库，并且是细胞内脂肪酸运输和信号传导的核心枢纽。脂解作用通过一种未知机制，经由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（MUFAs）通过变构激活SIRT1，使其作用于诸如PGC-1α等特定肽底物。MUFAs以SIRT1依赖性方式增强细胞和动物模型中的PGC-1α/PPARα信号传导并促进氧化代谢。此外，我们鉴定了脂滴蛋白围脂滴蛋白5（PLIN5），已知其可增强线粒体生物发生和功能，它是一种脂肪酸结合蛋白，优先结合源自脂滴的单不饱和脂肪酸，并在cAMP/PKA介导的脂解刺激后将它们转运至细胞核。因此，这些研究确定了SIRT1首个已知的内源性变构调节剂，并描述了一个脂滴-核信号轴，该轴是MUFAs和PLIN5已知代谢益处的基础。
