Introduction

Niemann-Pick C1 (NPC1), a lysosomal cholesterol transport protein, is required for efficient efferocytosis. Patients with Npc1 mutation are frequently accompanied with hepatic symptoms, including hepatomegaly, elevated liver transaminases, or even acute liver failure, but the pathogenic mechanism remains unknown.

Objectives

Our work aims to characterize the functional role of myeloid NPC1 in liver injury and elucidate its underlying mechanism.

Methods

Analyses of injured livers from patients with liver diseases and mouse models were conducted to examine NPC1 expression. Myeloid cell-specific Npc1 knockout mice were constructed to determine the functional role of macrophage NPC1 in liver injury. Isolated macrophages were subjected to in vitro mechanistical assays.

Results

We found that NPC1 is mainly expressed in hepatic macrophages. Its mRNA and protein expression are significantly elevated in injured livers from both patients and mouse models. Tissue-specific deletion of myeloid Npc1 increased liver inflammation, levels of serum liver function enzymes, and liver fibrosis in mouse models of liver injury induced by carbon tetrachloride (CCl₄) injection and methionine-and-choline-deficient (MCD) diets. Further analyses indicate that Npc1 deficiency in mouse models of liver injury resulted in increased levels of serum HMGB1 and mitochondrial DNA, promoted hepatic macrophage proinflammatory activation, M1 polarization, led to overproduction of hepatic inflammatory cytokines/chemokines, e.g. CCL2 and STING/NFκB pathway activation. In vitro mechanistical studies reveal that Npc1-deficient macrophages exhibited inefficient efferocytosis, partly due to impaired cargo degradation.

Conclusions

These findings indicate that elevated expression of myeloid NPC1 in liver diseases protects liver from injury by promoting macrophage efferocytosis of damaged cells. Dysfunction of NPC1 aggravates liver injury, suggesting that NPC1 may be a potential therapeutic target for treating liver diseases.

中文翻译：

---

髓系 NPC1 缺乏通过损害巨噬细胞胞吞作用加剧肝损伤和纤维化

 介绍

Niemann-Pick C1 （NPC1） 是一种溶酶体胆固醇转运蛋白，是高效泡腾作用所必需的。Npc1 突变患者常伴有肝脏症状，包括肝肿大、肝转氨酶升高，甚至急性肝功能衰竭，但致病机制尚不清楚。

 目标

我们的工作旨在表征髓系 NPC1 在肝损伤中的功能作用并阐明其潜在机制。

 方法

对肝病患者和小鼠模型受伤的肝脏进行分析，以检测 NPC1 的表达。构建髓系细胞特异性 Npc1 敲除小鼠以确定巨噬细胞 NPC1 在肝损伤中的功能作用。对分离的巨噬细胞进行体外机制测定。

 结果

我们发现 NPC1 主要在肝脏巨噬细胞中表达。其 mRNA 和蛋白质表达在患者和小鼠模型的受伤肝脏中均显著升高。在四氯化碳 （CCl₄） 注射和蛋氨酸和胆碱缺乏 （MCD） 饮食诱导的肝损伤小鼠模型中，髓系 Npc1 的组织特异性缺失增加了肝脏炎症、血清肝功能酶水平和肝纤维化。进一步分析表明，小鼠肝损伤模型中的 Npc1 缺陷导致血清 HMGB1 和线粒体 DNA 水平升高，促进肝脏巨噬细胞促炎激活，M1 极化，导致肝脏炎性细胞因子/趋化因子的过度产生，例如 CCL2 和 STING/NFκB 通路激活。体外机制研究表明，Npc1 缺陷的巨噬细胞表现出低效的胞吐作用，部分原因是货物降解受损。

 结论

这些发现表明，肝病中髓系 NPC1 表达升高通过促进受损细胞的巨噬细胞胞吐作用来保护肝脏免受损伤。NPC1 功能障碍加重肝损伤，提示 NPC1 可能是治疗肝脏疾病的潜在治疗靶点。