Kupffer细胞与肝细胞协作调控系统脂代谢平衡

There’s a growing appreciation that immunity and metabolism have extensive bidirectional communication and coordination. On one hand, cellular metabolism has direct roles in regulating immune cell activity and function. On the other hand, immune systems modulate diverse metabolic circuits. Macrophages are important components of the innate immune system. A number of studies have demonstrated that macrophages have key roles in systemic insulin resistance, glucose tolerance and the development of type 2 diabetes and other metabolic diseases. However, the homeostatic role of macrophages and the underlying mechanism in maintaining the systemic metabolism remain unclear for most tissues. Kupffer cells are liver resident macrophages, which represent the largest number of fixed tissue macrophages, but their specific involvement in the control of metabolic balance is incompletely defined. Our previous work suggest that Kupffer cells contribute to balanced lipid metabolism in steady state, possibly by regulating FGF21 expression in hepatocytes. Our study aims at ascertaining the role of “Kupffer cell-hepatocyte-FGF21” axis in lipolysis, and revealing an unappreciated mechanism by which Kupffer cell-mediated liver-adipose tissue crosstalk in maintaining systemic lipid metabolism.

免疫系统与代谢系统之间存在紧密的相互调控关系。一方面，代谢状态能够影响免疫细胞的活化和功能；另一方面，免疫系统又反过来调控机体代谢水平。巨噬细胞是免疫系统中重要的先天免疫细胞，大量研究表明巨噬细胞在系统性胰岛素抵抗，葡萄糖耐受，2型糖尿病和其它代谢性疾病的发生发展中均发挥重要作用。然而，在大多数组织中巨噬细胞对系统代谢稳态的调控及其机制还并不清晰。肝脏定居的Kupffer细胞，是体内数量最多的组织定居巨噬细胞，但人们对其在代谢稳态中的调控功能并不清楚。我们前期的结果提示，Kupffer细胞可能通过调控肝细胞中FGF21表达，进而抑制脂肪组织脂解，维持脂代谢稳态平衡。本项目将进一步确证“Kupffer细胞-肝细胞-FGF21”轴线对系统脂代谢的影响，从而揭示Kupffer细胞介导的肝脏-脂肪组织跨器官相互作用调控系统脂代谢的功能。

免疫系统与代谢系统之间存在紧密的相互调控关系。大量的研究发现多种免疫细胞，如巨噬细胞等是代谢稳态的重要调控者。肝脏作为重要的代谢和免疫器官，其组织定居的巨噬细胞Kupffer细胞在肝脏的生理及病理进程中均发挥重要作用。尽管Kupffer细胞在调控多种代谢失调等疾病中的功能被广泛研究，但是其在稳态条件下对系统代谢的影响及机制尚不清楚。我们的研究发现Kupffer细胞清除能够促进脂肪组织脂解。机制上，Kupffer细胞清除导致IL-1β表达降低，进而促进肝细胞中FGF21表达。肝细胞表达的FGF21进一步促进脂肪组织脂解，导致血脂升高及体重降低。本项目确证了Kupffer细胞与肝细胞互作调控系统脂代谢稳态的生理功能，并揭示了Kupffer细胞介导的肝脏-脂肪组织跨器官交流调控系统脂代谢的机制。