School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK.
Sci Adv. 2024 Sep 27;10(39):eadq3075. doi: 10.1126/sciadv.adq3075.
How cardiovascular activity interacts with lipid homeostasis is incompletely understood. We postulated a role for blood flow acting at endothelium in lipid regulatory organs. Transcriptome analysis was performed on livers from mice engineered for deletion of the flow-sensing PIEZO1 channel in endothelium. This revealed unique up-regulation of , which encodes the rate-limiting enzyme for bile synthesis from cholesterol in hepatocytes. Consistent with this effect were increased gallbladder and plasma bile acids and lowered hepatic and plasma cholesterol. Elevated portal fluid flow acting via endothelial PIEZO1 and genetically enhanced PIEZO1 conversely suppressed . Activation of hepatic endothelial PIEZO1 channels promoted phosphorylation of nitric oxide synthase 3, and portal flow-mediated suppression of depended on nitric oxide synthesis, suggesting endothelium-to-hepatocyte coupling via nitric oxide. variants in people were associated with hepatobiliary disease and dyslipidemia. The data suggest an endothelial force sensing mechanism that controls lipid regulation in parenchymal cells to modulate whole-body lipid homeostasis.
心血管活动与脂质动态平衡的相互作用尚不完全清楚。我们推测血流在脂质调节器官的内皮中的作用。对内皮中 PIEZO1 通道的流动感应缺失的小鼠进行肝脏转录组分析。这揭示了独特的上调，其编码了肝细胞中胆固醇转化为胆汁的限速酶。与这种作用一致的是，胆囊和血浆胆汁酸增加，肝和血浆胆固醇降低。通过内皮 PIEZO1 作用的升高的门静脉流体流动和遗传增强的 PIEZO1 相反地抑制。肝内皮 PIEZO1 通道的激活促进了一氧化氮合酶 3 的磷酸化，门静脉流量介导的 抑制取决于一氧化氮的合成，表明通过一氧化氮进行内皮细胞到肝细胞的偶联。人类中的 变体与肝胆疾病和血脂异常有关。这些数据表明了一种内皮力感应机制，它控制着实质细胞中的脂质调节，以调节全身脂质动态平衡。
