Rohrbach Timothy, Maceyka Michael, Spiegel Sarah
a Department of Biochemistry and Molecular Biology and the Massey Cancer Center , VCU School of Medicine , Richmond , VA , USA.
Crit Rev Biochem Mol Biol. 2017 Oct;52(5):543-553. doi: 10.1080/10409238.2017.1337706. Epub 2017 Jun 15.
Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1-5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases.
20多年前，1-磷酸鞘氨醇（S1P）被发现是一种生物活性信号分子。随后的研究鉴定出了两种相关激酶，即鞘氨醇激酶1和2，它们负责将鞘氨醇磷酸化为S1P。许多刺激会增加鞘氨醇激酶活性以及S1P的产生和分泌。在细胞外，S1P可以结合并激活五种S1P特异性G蛋白偶联受体（S1PR1-5），以自分泌或旁分泌方式调节许多重要的细胞和生理过程。S1P在血液中含量很高，其作用是控制血管完整性和淋巴细胞的运输。肥胖会增加人类和小鼠血液中的S1P水平。随着全球因食用高脂肪、高糖饮食导致肥胖人数的增加，S1P正成为肝脏病理生物学的帮凶，包括急性肝衰竭、代谢综合征、血脂和葡萄糖稳态的控制、非酒精性脂肪性肝病以及肝纤维化。在此，我们综述了鞘氨醇激酶、S1P和S1PRs在肝脏病理生物学中的重要性的最新研究，重点关注针对多种肝脏疾病靶向S1P信号轴的新治疗方式的令人兴奋的见解。
