The CC motif chemokine ligand 11 contributes to alcoholic liver disease

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-01-20 DOI:10.1016/j.lfs.2025.123409

Jichen Li , Ben Wang , Shunjie Wang , Jieguo Wang , Anqi Zhou , Shanwen Gong , Yu Wang , Xiulian Miao , Yan Guo , Hao Wang , Hailong Ge

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Abstract

Aims

Alcoholic liver disease (ALD) is characterized by aberrant lipid metabolism and chronic inflammation that eventually give rise to cirrhosis and hepatocellular carcinoma. In the present study we investigated the contribution of CC motif chemokine ligand 11 (CCL11) to ALD pathogenesis.

Methods and materials

ALD was induced in mice by binge ethanol gavage or chronic ethanol feeding.

Key findings

Bioinformatic analysis of sequencing data indicated that CCL11 expression was up-regulated in hepatocytes from mice subjected to ethanol feeding compared to those from the control mice. Exposure to ethanol led to CCL11 up-regulation in primary murine hepatocytes in vitro. Consistently, Oil Red O (ORO) staining detected elevated lipid accumulation whereas quantitative PCR (qPCR) detected augmented expression of pro-inflammatory mediators in primary murine hepatocytes treated with recombinant CCL11. On the contrary, CCL11 knockout mice (KO) developed a less severe form of ALD compared to wild type littermates when subjected to either binge or chronic ethanol feeding. Finally, CCL11 antagonism by administration with an inhibitor to CCL11 receptor CCR3 (CCR3i) attenuated ALD in mice.

Significance

Our data support a role for CCL11 in ALD pathogenesis and provide proof-of-concept that targeting CCL11 can be considered as a therapeutic approach for ALD intervention.

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CC基序趋化因子配体11与酒精性肝病有关。

目的：酒精性肝病（ALD）以脂质代谢异常和慢性炎症为特征，最终导致肝硬化和肝细胞癌。在本研究中，我们研究了CC基序趋化因子配体11 （CCL11）在ALD发病中的作用。方法与材料：采用乙醇灌胃法和慢性乙醇喂养法诱导小鼠ALD。主要发现：测序数据的生物信息学分析表明，与对照组小鼠相比，乙醇喂养小鼠肝细胞中的CCL11表达上调。乙醇暴露导致体外小鼠原代肝细胞CCL11表达上调。同样，油红O （ORO）染色检测到脂质积累升高，而定量PCR （qPCR）检测到重组CCL11处理的原代小鼠肝细胞中促炎介质的表达增强。相反，CCL11基因敲除小鼠（KO）在暴食或慢性乙醇喂养时，与野生型小鼠相比，ALD的严重程度较轻。最后，通过给药CCL11受体抑制剂（CCR3i）来拮抗CCL11，可以减轻小鼠的ALD。意义：我们的数据支持CCL11在ALD发病机制中的作用，并提供了靶向CCL11可被视为ALD干预的治疗方法的概念证明。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.