Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner

IF 10.1 1区 工程技术 Q1 ENGINEERING, MULTIDISCIPLINARY
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Abstract

Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.
PKM2 的治疗靶点能以巨噬细胞特异性和肝脏特异性方式改善 NASH 纤维化进展
非酒精性脂肪性肝炎(NASH)可能很快就会成为全球终末期肝病的主要病因,但治疗方法却很有限。慢性炎症和肝星状细胞(HSC)活化导致的肝纤维化严重影响了非酒精性脂肪性肝炎患者的发病率和死亡率。丙酮酸激酶M2(PKM2)参与了免疫激活和炎症性肝病;然而,它在与NASH相关的肝纤维化中的作用和治疗潜力在很大程度上仍未得到探索。对人类和鼠类 NASH 肝脏进行的生物信息学筛选和分析表明,在纤维化 NASH 患者的肝脏中,PKM2 在非实质细胞(NPC),尤其是巨噬细胞中上调。在蛋氨酸和胆碱缺乏(MCD)饮食、高脂高胆固醇(HFHC)饮食和西式饮食加每周注射四氯化碳(WD/CCl4)诱导的三种不同的NASH模型中,巨噬细胞特异性PKM2基因敲除(PKM2FL/FLLysM-Cre)能显著改善肝脏炎症和纤维化的严重程度。单细胞转录组分析表明,巨噬细胞中PKM2的缺失减少了Ly6Chigh巨噬细胞的浸润。从机制上讲,PKM2依赖性糖酵解促进了促炎巨噬细胞中NLR家族含吡咯啉结构域3(NLRP3)的活化,从而诱导了造血干细胞的活化和纤维化。一种药理 PKM2 激动剂能有效减轻巨噬细胞和造血干细胞之间在体外和体内的损伤性串联。胆固醇共轭杂合双寡核苷酸是一种新型寡核苷酸药物,可优先在肝脏中蓄积,它可通过剂量依赖性地逆转与 NASH 相关的纤维化,且不会引起明显的肝毒性。本研究强调了巨噬细胞PKM2在推进NASH纤维化过程中的关键作用。因此,以巨噬细胞特异性或肝脏特异性的方式对PKM2进行治疗调节可能会成为抗击NASH相关纤维化的一种新策略。
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来源期刊
Engineering
Engineering Environmental Science-Environmental Engineering
自引率
1.60%
发文量
335
审稿时长
35 days
期刊介绍: Engineering, an international open-access journal initiated by the Chinese Academy of Engineering (CAE) in 2015, serves as a distinguished platform for disseminating cutting-edge advancements in engineering R&D, sharing major research outputs, and highlighting key achievements worldwide. The journal's objectives encompass reporting progress in engineering science, fostering discussions on hot topics, addressing areas of interest, challenges, and prospects in engineering development, while considering human and environmental well-being and ethics in engineering. It aims to inspire breakthroughs and innovations with profound economic and social significance, propelling them to advanced international standards and transforming them into a new productive force. Ultimately, this endeavor seeks to bring about positive changes globally, benefit humanity, and shape a new future.
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