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.

肝脏内的肝细胞具有巨大的适应营养供应变化的能力。在这里，通过使用高分辨率体积电子显微镜，我们绘制了在营养波动期间肝亚细胞空间组织如何调节以及作为肝脏分区的函数的图谱。我们发现禁食会导致肝细胞内质网 (ER) 结构的重塑，其特征是在线粒体周围诱导单个粗糙的 ER 片层，使其变得更大、更平坦。这些改变在门静脉周围和中小叶肝细胞中丰富，但在中央周围肝细胞中不丰富。体内功能获得和丧失模型表明，核糖体受体结合蛋白 1 (RRBP1) 是实现禁食诱导的 ER 片层-线粒体相互作用和调节肝脂肪酸氧化所必需的。内源性 RRBP1 在肝脏的门静脉周围和中小叶区域富集。在肥胖症中，内质网-线粒体相互作用是明显的，禁食不能诱导粗略的内质网片层-线粒体相互作用。这些发现说明了受调控的分子结构对于肝细胞代谢灵活性的重要性。