Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein [snRNA-seq]

The liver is essential for normal fatty acid utilization during fasting. Circulating fatty acids are taken up by hepatocytes and esterified as triacylglycerols for either oxidative metabolization and ketogenesis or export. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, the uptake and retention of non-esterified fatty acids by hepatocytes is not. Here, we show that murine hepatic stellate cells (HSCs) and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic substrate preference for fasting energy metabolism. HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance. Fasted HSC PLVAP knockout mice showed suppressed hepatic fatty acid esterification to di- and triacylglycerols shifting fasting metabolism from fatty acid oxidation to reliance on carbohydrates. By super-resolution microscopy we localized HSC PLVAP to caveolae residing along the sinusoidal lumen supporting a role for HSCs and PLVAP-diaphragmed caveolae in normal fasting metabolism of the liver. 10x Genomics single-nucleus RNA-sequencing of fasted littermate control and HSC-Plvap knockout mice肝脏在禁食状态下的正常脂肪酸利用过程中发挥关键作用。循环中的脂肪酸被肝细胞摄取，并酯化为三酰甘油，用于氧化代谢与生酮作用，或是被分泌输出。尽管肝细胞内脂肪酸氧化的调控机制已被充分阐明，但肝细胞对未酯化脂肪酸的摄取与滞留过程仍未得到清晰解析。本研究表明，小鼠肝星状细胞（hepatic stellate cells, HSCs）及其高表达的质膜囊泡相关蛋白（plasmalemma vesicle-associated protein, PLVAP）可调控肝脏在禁食能量代谢中的底物偏好。在小鼠体内特异性敲除HSCs中的PLVAP，可增强肝脏胰岛素信号通路并改善糖耐量。禁食状态下，HSC-PLVAP敲除小鼠的肝脏脂肪酸酯化生成二酰甘油与三酰甘油的过程受到抑制，使禁食代谢模式从脂肪酸氧化转向依赖碳水化合物。通过超分辨率显微镜，我们将HSCs表达的PLVAP定位于沿血窦腔分布的胞膜窖中，这提示HSCs与带有PLVAP隔膜的胞膜窖在肝脏正常禁食代谢中发挥功能。本研究对禁食状态下的同窝对照小鼠与HSC-Plvap敲除小鼠开展了10x Genomics单细胞核RNA测序。