Department of Molecular Metabolism and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
Nat Commun. 2024 May 10;15(1):3982. doi: 10.1038/s41467-024-48272-7.
The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.
肝脏中的肝细胞具有巨大的适应营养供应变化的能力。在这里，我们通过使用高分辨率体积电子显微镜，描绘了肝亚细胞空间组织如何在营养波动和肝区带功能中进行调节。我们发现，禁食导致肝细胞内质网（ER）结构的重塑，其特征是在靠近线粒体的地方诱导单个粗糙 ER 片，该 ER 片变得更大更平。这些改变在门脉周围和中肝小叶细胞中富集，但不在中央静脉周围细胞中富集。体内的 gain-和 loss-of-function 模型表明，核糖体受体结合蛋白 1（RRBP1）是必需的，以实现禁食诱导的 ER 片-线粒体相互作用，并调节肝脂肪酸氧化。内源性 RRBP1 在肝的门脉周围和中肝小叶区域富集。在肥胖中，ER-线粒体相互作用是不同的，禁食不能诱导粗糙 ER 片-线粒体相互作用。这些发现说明了调节分子结构对于肝细胞代谢灵活性的重要性。
