Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein [bulk RNA-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. Overall design: Bulk RNA-sequencing from fasted or refed HSC-Plvap-knockout mice, Cav1-knockout mice, and control mice Bulk RNA-sequencing from over-night fasted HSC-Plvap-knockout and control mice given six weeks of either western diet or high-fat diet

肝脏在禁食状态下的正常脂肪酸利用过程中至关重要。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、生酮作用或分泌输出。目前学界对肝细胞内脂肪酸氧化的调控机制已有充分认知，但肝细胞对非酯化脂肪酸的摄取与滞留过程仍未明确。本研究证实，小鼠肝星状细胞（murine 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。小鼠体内HSC特异性敲除PLVAP后，肝脏胰岛素信号通路活性升高，葡萄糖耐受能力得到改善。禁食状态下的HSC PLVAP敲除小鼠，其肝脏内脂肪酸酯化为二酰甘油与三酰甘油的过程受到抑制，使得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技术，我们将HSC表达的PLVAP定位于沿血窦管腔分布的窖小窝（caveolae），这提示HSCs与PLVAP包被的窖小窝在肝脏正常禁食代谢中发挥作用。整体实验设计：分别对禁食或复食的HSC-Plvap敲除小鼠、Cav1敲除小鼠及对照小鼠开展批量RNA测序；同时对饲喂西式饮食或高脂饮食六周后的过夜禁食HSC-Plvap敲除小鼠与对照小鼠进行批量RNA测序。