Deficiency of myeloid NPC1 exacerbates liver injury and fibrosis by impairing macrophage efferocytosis

Dongwei Guan; Pengju Huang; Xinlei Liu; Qing Li; Xiaoxun Zhang; Nan Liu; Yong Wang; Ying Wan; Jin Chai; Shiying Cai; Rui Chen; Zhijia Ye

doi:10.1016/j.jare.2024.11.020

Deficiency of myeloid NPC1 exacerbates liver injury and fibrosis by impairing macrophage efferocytosis

J Adv Res. 2024 Nov 14:S2090-1232(24)00539-3. doi: 10.1016/j.jare.2024.11.020. Online ahead of print.

Authors

Dongwei Guan¹, Pengju Huang², Xinlei Liu², Qing Li², Xiaoxun Zhang³, Nan Liu⁴, Yong Wang⁵, Ying Wan⁶, Jin Chai³, Shiying Cai⁷, Rui Chen⁸, Zhijia Ye⁹

Affiliations

¹ Laboratory Animal Research Center, School of Medicine, Chongqing University, Chongqing 400044, China. Electronic address: dwguan@cqu.edu.cn.
² Laboratory Animal Research Center, School of Medicine, Chongqing University, Chongqing 400044, China.
³ Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center and Center for Metabolic-Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China.
⁴ Department of Urology Oncological Surgery, Chongqing University Cancer Hospital, Chongqing 400030, China.
⁵ Department of Laboratory Animal Science, Third Military Medical University (Army Medical University), Chongqing 400038, China.
⁶ Biomedical Analysis Center, Third Military Medical University (Army Medical University), Chongqing 400038, China.
⁷ Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA.
⁸ Department of Pathology, Chongqing University Cancer Hospital, Chongqing 400030, China. Electronic address: chenrui76@cqu.edu.cn.
⁹ Laboratory Animal Research Center, School of Medicine, Chongqing University, Chongqing 400044, China. Electronic address: yezj918@cqu.edu.cn.

PMID: 39547438
DOI: 10.1016/j.jare.2024.11.020

Abstract

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.

Keywords: Efferocytosis; Liver fibrosis; Liver injury; Macrophage; NPC1.