Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China.
Cell Mol Gastroenterol Hepatol. 2024;17(6):1039-1061. doi: 10.1016/j.jcmgh.2024.03.002. Epub 2024 Mar 11.
BACKGROUND & AIMS: The functional maturation of the liver largely occurs after birth. In the early stages of life, the liver of a newborn encounters enormous high-fat metabolic stress caused by the consumption of breast milk. It is unclear how the maturing liver adapts to high lipid metabolism. Liver sinusoidal endothelial cells (LSECs) play a fundamental role in establishing liver vasculature and are decorated with many glycoproteins on their surface. The Slc35a1 gene encodes a cytidine-5'-monophosphate (CMP)-sialic acid transporter responsible for transporting CMP-sialic acids between the cytoplasm and the Golgi apparatus for protein sialylation. This study aimed to determine whether endothelial sialylation plays a role in hepatic vasculogenesis and functional maturation.
Endothelial-specific Slc35a1 knockout mice were generated. Liver tissues were collected for histologic analysis, lipidomic profiling, RNA sequencing, confocal immunofluorescence, and immunoblot analyses.
Endothelial Slc35a1-deficient mice exhibited excessive neonatal hepatic lipid deposition, severe liver damage, and high mortality. Endothelial deletion of Slc35a1 led to sinusoidal capillarization and disrupted hepatic zonation. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) in LSECs was desialylated and VEGFR2 signaling was enhanced in Slc35a1-deficient mice. Inhibition of VEGFR2 signaling by SU5416 alleviated lipid deposition and restored hepatic vasculature in Slc35a1-deficient mice.
Our findings suggest that sialylation of LSECs is critical for maintaining hepatic vascular development and lipid homeostasis. Targeting VEGFR2 signaling may be a new strategy to prevent liver disorders associated with abnormal vasculature and lipid deposition.
肝脏的功能成熟主要发生在出生后。在生命的早期阶段，新生儿的肝脏会因食用母乳而面临巨大的高脂肪代谢应激。目前尚不清楚成熟的肝脏如何适应高脂质代谢。肝窦内皮细胞（LSEC）在建立肝脏脉管系统方面发挥着基本作用，其表面有许多糖蛋白。Slc35a1 基因编码一种胞苷-5'-单磷酸（CMP）-唾液酸转运蛋白，负责将 CMP-唾液酸在细胞质和高尔基体之间运输，用于蛋白质唾液酸化。本研究旨在确定内皮细胞唾液酸化是否在肝血管生成和功能成熟中发挥作用。
生成内皮细胞特异性 Slc35a1 敲除小鼠。收集肝组织进行组织学分析、脂质组学分析、RNA 测序、共聚焦免疫荧光和免疫印迹分析。
内皮细胞 Slc35a1 缺失的小鼠表现出新生肝脂质沉积过多、严重肝损伤和高死亡率。内皮细胞 Slc35a1 的缺失导致肝窦毛细血管化和肝区带结构破坏。机制上，LSEC 中的血管内皮生长因子受体 2（VEGFR2）发生去唾液酸化，Slc35a1 缺陷小鼠的 VEGFR2 信号增强。通过 SU5416 抑制 VEGFR2 信号可减轻 Slc35a1 缺陷小鼠的脂质沉积并恢复肝血管。
我们的研究结果表明，LSEC 的唾液酸化对于维持肝脏血管发育和脂质稳态至关重要。靶向 VEGFR2 信号可能是预防与异常血管和脂质沉积相关的肝脏疾病的新策略。
