将抑制肝脏 PCSK9 作为新的治疗靶点可改善小鼠的代谢性脂肪性肝炎。

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-11-16 DOI:10.1016/j.intimp.2024.113621

Tuoluonayi Mijiti , Xiaocui Chen , Xiang Ma , Yitong Ma , Xiumin Ma , Bangdang Chen

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引用次数: 0

摘要

背景与目的：代谢性脂肪性肝炎（MASH）与代谢紊乱密切相关，其主要特征是肝细胞脂肪变性，伴有肝细胞损伤和炎症。严重的 MASH 可发展为肝硬化。目前，还没有治疗 MASH 的有效方法。Proprotein convertase subtilisin/kexin 9（PCSK9）是开发降胆固醇药物和治疗干预心血管疾病的热门靶点。本研究旨在探讨PCSK9在蛋氨酸和胆碱缺乏（MCD）饮食诱导的MASH进展中的作用及其靶向干预：方法：在MASH小鼠模型中测定PCSK9的表达，并使用PCSK9基因敲除（PCSK9-/-）小鼠饲喂MCD饮食研究PCSK9在调节脂质代谢、炎症和纤维化中的作用。研究使用腺相关病毒改变MASH小鼠中PCSK9的表达：结果：C57BL/6J野生型（WT）小鼠摄入MCD饮食后，出现明显的脂肪性肝炎、肝脏PCSK9表达和循环中PCSK9表达升高。PCSK9-/- 小鼠的血清谷丙转氨酶（ALT）水平降低，血清谷草转氨酶（AST）水平降低，肝脏空泡变小，肝脏脂质沉积减少，MCD 诱导的肝脂肪变明显减轻。以 MCD 为食的 PCSK9-/- 小鼠的炎症和纤维化程度明显降低。此外，腺相关病毒（AAV）介导的小鼠肝脏 PCSK9 沉默也能明显缓解肝脏脂肪变性、炎症和纤维化：本研究证明了 PCSK9 在 MASH 中的重要作用，表明抑制 PCSK9 可能是治疗 MASH 的一种有效的新疗法。

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Inhibition of hepatic PCSK9 as a novel therapeutic target ameliorates metabolic steatohepatitis in mice

Background & Aims

Metabolic steatohepatitis (MASH) is closely related to metabolic disorders, and the main characteristics of MASH are hepatocyte steatosis with hepatocyte injury and inflammation. In severe cases, MASH can develop into liver cirrhosis. At present, there is no effective treatment for MASH. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a popular target for the development of cholesterol-lowering drugs and therapeutic interventions for cardiovascular disease. The present study aimed to explore the role of PCSK9 in methionine- and choline-deficient (MCD) diet-induced MASH progression and its targeted intervention.

Methods

PCSK9 expression was determined in a MASH mouse model, and the role of PCSK9 in the regulation of lipid metabolism, inflammation, and fibrosis was investigated using PCSK9 knockout (PCSK9^−/−) mice fed a MCD diet. An adeno-associated virus was used to alter PCSK9 expression in MASH mice.

Results

Following the MCD diet, C57BL/6J wild-type (WT) mice developed marked steatohepatitis and elevated hepatic PCSK9 expression, and circulating PCSK9 expression. PCSK9^−/− mice showed significantly alleviated MCD-induced hepatic steatosis, with lower serum ALT levels, lower serum AST levels, smaller hepatic vacuoles, and less hepatic lipid deposition. PCSK9^−/− mice on the MCD diet showed a significantly reduced levels of inflammation and fibrogenesis. Moreover, adeno-associated virus (AAV)–mediated PCSK9 silencing in mouse livers significantly relieved liver steatosis, inflammation, and fibrosis.

Conclusions

The present study demonstrated an important role of PCSK9 in MASH, suggesting that inhibition of PCSK9 may represent a novel and effective therapeutic strategy for MASH treatment.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.