RRC ID 81440
Author Yanagisawa H, Maeda H, Noguchi I, Tanaka M, Wada N, Nagasaki T, Kobayashi K, Kanazawa G, Taguchi K, Chuang VTG, Sakai H, Nakashima H, Kinoshita M, Kitagishi H, Iwakiri Y, Sasaki Y, Tanaka Y, Otagiri M, Watanabe H, Maruyama T.
Title Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation.
Journal Redox Biol
Abstract 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.
Volume 76
Pages 103314
Published 2024-8-17
DOI 10.1016/j.redox.2024.103314
PII S2213-2317(24)00292-1
PMID 39163766
PMC PMC11381851
MeSH AMP-Activated Protein Kinases* / metabolism Animals Carbon Monoxide* / metabolism Diet, High-Fat / adverse effects Disease Models, Animal* Erythrocytes* / metabolism Heme Oxygenase-1 / metabolism Humans Kupffer Cells* / metabolism Liver / metabolism Liver / pathology Male Mice Non-alcoholic Fatty Liver Disease* / etiology Non-alcoholic Fatty Liver Disease* / metabolism Oxidative Stress / drug effects
IF 9.986
Resource
Human and Animal Cells RAW 264(RCB0535) Hep G2(RCB1886)