Acer3/ULCCs代谢在调控Kupffer细胞极化影响肝切除术后肝再生的关键作用及机制研究

肝再生障碍是肝切除术后致死性并发症“肝切除术后肝功能不全（PHI）”的重要机制。Kupffer细胞极化在调控肝再生的作用及机制尚未明确。碱性神经酰胺酶3（ACER3）是特异性降解不饱和长链神经酰胺（ULCCs）的关键酶。我们率先报道Acer3参与调控巨噬细胞极化，Acer3的基因敲除引起ULCCs降解障碍，促进巨噬细胞M1极化，加重组织炎症损伤。预实验进一步显示Acer3介导的ULCCs代谢是调控Kupffer细胞M1、M2极化的重要阀门；而Acer3的全身性基因敲除导致残余肝组织ULCCs上调，促进Kupffer细胞M1极化、抑制其M2极化，激化炎症损伤，抑制肝再生，加重PHI。本课题将通过构建Kupffer细胞特异性Acer3基因敲除小鼠，重点阐明Acer3介导的ULCCs代谢在调控Kupffer细胞极化影响肝切除术后肝再生的作用及机制，为理解PHI的机制及其防治提供新思路。

Post-hepatectomy hepatic insufficiency (PHI) is a life-threatening complication after liver resection. Disorder of hepatic regeneration has been implicated to promote the development and progression of PHI. Kupffer cells are major macrophages in liver, but the role of Kupffer cell polarization in liver regeneration has not yet been well elucidated. Alkaline ceramidase 3 (ACER3) is the key enzyme that specifically hydrolyzes unsaturated long-chain ceramides (ULCCs). We were the first to report that Acer3 is involved in regulating macrophage polarization, knockout of Acer3 resulted in deficiency of ULCCs degradation, which promoted M1 macrophage polarization to aggravate inflammatory damage. Our preliminary experiments further showed that the Acer3-mediated metabolism of ULCCs also plays an important role in regulating polarization of Kupffer cells. Systemic knockout of Acer3 suppressed ULCCs degradation and promoted polarization of M1 Kupffer cells in liver tissue after hepatectomy while inhibiting polarization of M2 Kupffer cells, resulting in augmentation in inflammation damage, inhibition of liver regeneration, and eventually aggravation in PHI. By establishing Kupffer-cell-specific Acer3 knockout mice, this project aims to study the role and mechanism of Acer3-mediated metabolism of ULCCs in regulating Kupffer cell polarization to affect liver regeneration and PHI, which will provide new ideas for understanding the mechanism and therapy of PHI.