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Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation
Redox Biology ( IF 10.7 ) Pub Date : 2024-08-17 , DOI: 10.1016/j.redox.2024.103314
Hiroki Yanagisawa 1 , Hitoshi Maeda 1 , Isamu Noguchi 1 , Motohiko Tanaka 2 , Naoki Wada 1 , Taisei Nagasaki 1 , Kazuki Kobayashi 1 , Gai Kanazawa 1 , Kazuaki Taguchi 3 , Victor Tuan Giam Chuang 4 , Hiromi Sakai 5 , Hiroyuki Nakashima 6 , Manabu Kinoshita 6 , Hiroaki Kitagishi 7 , Yasuko Iwakiri 8 , Yutaka Sasaki 9 , Yasuhito Tanaka 9 , Masaki Otagiri 10 , Hiroshi Watanabe 11 , Toru Maruyama 1
Affiliation  

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of nonalcoholic fatty liver disease characterised by fat accumulation, inflammation, oxidative stress, fibrosis, and impaired liver regeneration. In this study, we found that heme oxygenase-1 (HO-1) is induced in both MASH patients and in a MASH mouse model. Further, hepatic carbon monoxide (CO) levels in MASH model mice were >2-fold higher than in healthy mice, suggesting that liver HO-1 is activated as MASH progresses. Based on these findings, we used CO-loaded red blood cells (CO-RBCs) as a CO donor in the liver, and evaluated their therapeutic effect in methionine-choline deficient diet (MCDD)-induced and high-fat-diet (HFD)-induced MASH model mice. Intravenously administered CO-RBCs effectively delivered CO to the MASH liver, where they prevented fat accumulation by promoting fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor induction. They also markedly suppressed Kupffer cell activation and their corresponding anti-inflammatory and antioxidative stress activities in MASH mice. CO-RBCs also helped to restore liver regeneration in mice with HFD-induced MASH by activating AMPK. We confirmed the underlying mechanisms by performing in vitro experiments in RAW264.7 cells and palmitate-stimulated HepG2 cells. Taken together, CO-RBCs show potential as a promising cellular treatment for MASH.

中文翻译:


负载一氧化碳的红细胞通过增强 AMP 激活蛋白激酶活性和抑制库普弗细胞激活来改善代谢功能障碍相关的脂肪性肝炎进展



代谢功能障碍相关脂肪性肝炎 (MASH) 是一种进行性的非酒精性脂肪肝疾病,其特征是脂肪堆积、炎症、氧化应激、纤维化和肝再生受损。在这项研究中,我们发现 MASH 患者和 MASH 小鼠模型中都会诱导血红素加氧酶-1 (HO-1)。此外,MASH 模型小鼠的肝脏一氧化碳 (CO) 水平比健康小鼠高 >2 倍,表明肝脏 HO-1 随着 MASH 的进展而被激活。基于这些发现,我们使用负载CO的红细胞(CO-RBC)作为肝脏中的CO供体,并评估了它们对蛋氨酸胆碱缺乏饮食(MCDD)诱导的和高脂肪饮食(HFD)的治疗效果。 )诱导的MASH模型小鼠。静脉注射 CO-RBC 有效地将 CO 输送到 MASH 肝脏,在肝脏中,它们通过 AMP 激活蛋白激酶 (AMPK) 激活和过氧化物酶体增殖物激活受体诱导促进脂肪酸氧化,从而防止脂肪积累。他们还显着抑制了 MASH 小鼠中库普弗细胞的活化及其相应的抗炎和抗氧化应激活性。 CO-RBC 还通过激活 AMPK 帮助恢复 HFD 诱导的 MASH 小鼠的肝再生。我们通过在 RAW264.7 细胞和棕榈酸酯刺激的 HepG2 细胞中进行体外实验证实了潜在的机制。总而言之,CO-RBC 显示出作为 MASH 细胞治疗的有前景的潜力。
更新日期:2024-08-17
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