Glycogen synthase kinase 3 activity enhances liver inflammation in MASH

IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY JHEP Reports Pub Date : 2024-06-01 DOI:10.1016/j.jhepr.2024.101073
Mireille Khoury , Qianqian Guo , Kunimaro Furuta , Cristina Correia , Chady Meroueh , Hyun Se Kim Lee , Khaled Warasnhe , Lucía Valenzuela-Pérez , Andrew P. Mazar , Iljung Kim , Yung-Kyun Noh , Heather Holmes , Michael F. Romero , Caroline R. Sussman , Kevin D. Pavelko , Shahidul Islam , Adebowale O. Bamidele , Petra Hirsova , Hu Li , Samar H. Ibrahim
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Abstract

Background & Aims

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to liver sinusoidal endothelial cells (LSECs) and transendothelial migration (TEM) are crucial in the inflammatory process. Under lipotoxic stress, LSECs develop a proinflammatory phenotype known as endotheliopathy. However, mediators of endotheliopathy remain unclear.

Methods

Primary mouse LSECs isolated from C57BL/6J mice fed chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH resulting from a choline-deficient high-fat diet (CDHFD) or FFC diet were also treated with two structurally distinct GSK3 inhibitors (LY2090314 and elraglusib [9-ING-41]).

Results

Integrated pathway analysis of the mouse LSEC proteome and transcriptome indicated that leukocyte TEM and focal adhesion were the major pathways altered in MASH. Kinome profiling of the LSEC phosphoproteome identified glycogen synthase kinase (GSK)-3β as the major kinase hub in MASH. GSK3β-activating phosphorylation was increased in primary human LSECs treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependent mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through the LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC- and CDHFD-fed mice, respectively. Immunophenotyping using cytometry by mass cytometry by time of flight of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib showed reduced infiltration of proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells.

Conclusion

GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and could serve as a potential therapeutic strategy for treating human MASH.

Impact and Implications

LSECs under lipotoxic stress in MASH develop a proinflammatory phenotype known as endotheliopathy, with obscure mediators and functional outcomes. The current study identified GSK3 as the major driver of LSEC endotheliopathy, examined its pathogenic role in myeloid cell-associated liver inflammation, and defined the therapeutic efficacy of pharmacological GSK3 inhibitors in murine MASH. This study provides preclinical data for the future investigation of GSK3 pharmacological inhibitors in human MASH. The results of this study are important to hepatologists, vascular biologists, and investigators studying the mechanisms of inflammatory liver disease and MASH, as well as those interested in drug development.

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糖原合成酶激酶 3 的活性可增强 MASH 的肝脏炎症反应
背景& 目的代谢功能障碍相关性脂肪性肝炎(MASH)的特点是循环中有毒脂质过多、肝脏脂肪变性和肝脏炎症。单核细胞粘附到肝窦状内皮细胞(LSECs)和跨内皮迁移(TEM)在炎症过程中至关重要。在脂毒性压力下,肝窦内皮细胞会形成一种促炎症表型,即内皮病变。方法对从喂食饲料或富含脂肪、果糖和胆固醇(FFC)的 MASH 诱导饮食的 C57BL/6J 小鼠体内分离出的原代小鼠 LSECs 进行多组学分析。结果小鼠LSEC蛋白质组和转录组的整合通路分析表明,白细胞TEM和病灶粘附是MASH改变的主要通路。LSEC磷酸蛋白组的激酶组分析确定糖原合酶激酶(GSK)-3β是MASH的主要激酶枢纽。在使用有毒脂质棕榈酸酯处理的原代人LSEC和人MASH中,GSK3β激活磷酸化增加。棕榈酸酯通过 GSK3 依赖性机制上调了 C-X-C motif 趋化因子配体 2、细胞内粘附分子 1 和磷酸化焦点粘附激酶的表达。同样,在脂毒性胁迫下,GSK3抑制剂降低了原代人中性粒细胞和THP-1单核细胞通过LSEC单层的粘附和跨内皮迁移能力。GSK3抑制剂LY2090314和elraglusib可分别改善FFC和CDHFD喂养小鼠的肝脏炎症、损伤和纤维化。使用埃拉格鲁西布治疗的 CDHFD 喂养小鼠肝内白细胞飞行时间质谱细胞计数法进行的免疫分型显示,促炎性单核细胞衍生巨噬细胞和单核细胞衍生树突状细胞的浸润减少。影响和意义LSECs 在 MASH 脂肪毒性应激下会形成一种促炎症表型,即内皮病变,其介质和功能结果不明显。目前的研究发现 GSK3 是 LSEC 内皮细胞病变的主要驱动因素,研究了 GSK3 在髓细胞相关肝脏炎症中的致病作用,并确定了 GSK3 药理抑制剂在小鼠 MASH 中的疗效。这项研究为今后研究 GSK3 药理抑制剂在人类 MASH 中的应用提供了临床前数据。这项研究的结果对于肝病学家、血管生物学家、研究炎症性肝病和MASH机制的研究人员以及对药物开发感兴趣的人来说非常重要。
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来源期刊
JHEP Reports
JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
12.40
自引率
2.40%
发文量
161
审稿时长
36 days
期刊介绍: JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.
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Contents Editorial Board page Copyright and information Contents ALT levels, alcohol use, and metabolic risk factors have prognostic relevance for liver-related outcomes in the general population
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