Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China.
Adv Sci (Weinh). 2024 Nov;11(41):e2405240. doi: 10.1002/advs.202405240. Epub 2024 Sep 5.
Spatial heterogeneity and plasticity of the mammalian liver are critical for systemic metabolic homeostasis in response to fluctuating nutritional conditions. Here, a spatially resolved transcriptomic landscape of mouse livers across fed, fasted and refed states using spatial transcriptomics is generated. This approach elucidated dynamic temporal-spatial gene cascades and how liver zonation-both expression levels and patterns-adapts to shifts in nutritional status. Importantly, the pericentral nuclear receptor Nr1i3 (CAR) as a pivotal regulator of triglyceride metabolism is pinpointed. It is showed that the activation of CAR in the pericentral region is transcriptionally governed by Pparα. During fasting, CAR activation enhances lipolysis by upregulating carboxylesterase 2a, playing a crucial role in maintaining triglyceride homeostasis. These findings lay the foundation for future mechanistic studies of liver metabolic heterogeneity and plasticity in response to nutritional status changes, offering insights into the zonated pathology that emerge during liver disease progression linked to nutritional imbalances.
哺乳动物肝脏的空间异质性和可塑性对于应对波动的营养条件下的全身代谢稳态至关重要。在这里，使用空间转录组学生成了一张关于小鼠肝脏在进食、禁食和再进食状态下的空间转录组学全景图。这种方法阐明了动态时空基因级联反应，以及肝分区 - 表达水平和模式 - 如何适应营养状况的变化。重要的是，确定了中央核受体 Nr1i3（CAR）作为甘油三酯代谢的关键调节剂。研究表明，中央区 CAR 的激活受 Pparα 的转录控制。在禁食期间，CAR 的激活通过上调羧酸酯酶 2a 增强脂肪分解，在维持甘油三酯稳态方面发挥着关键作用。这些发现为未来研究营养状态变化时肝脏代谢异质性和可塑性的机制奠定了基础，为与营养失衡相关的肝脏疾病进展过程中出现的分区病理提供了新的见解。
