Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation
Hiroki Yanagisawa,
Hitoshi Maeda,
Isamu Noguchi,
Motohiko Tanaka,
Naoki Wada,
Taisei Nagasaki,
Kazuki Kobayashi,
Gai Kanazawa,
Kazuaki Taguchi,
Victor Tuan Giam Chuang,
Hiromi Sakai,
Hiroyuki Nakashima,
Manabu Kinoshita,
Hiroaki Kitagishi,
Yasuko Iwakiri,
Yutaka Sasaki,
Yasuhito Tanaka,
Masaki Otagiri,
Hiroshi Watanabe,
Toru Maruyama
Affiliations
Hiroki Yanagisawa
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Hitoshi Maeda
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Isamu Noguchi
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Motohiko Tanaka
Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Gastroenterology and Hepatology, Saiseikai Kumamoto Hospital, Kumamoto, Japan
Naoki Wada
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Taisei Nagasaki
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Kazuki Kobayashi
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Gai Kanazawa
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Kazuaki Taguchi
Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
Victor Tuan Giam Chuang
Pharmacy Discipline, Curtin Medical School, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, 6845, Western Australia, Australia
Hiromi Sakai
Department of Chemistry, Nara Medical University, Nara, Japan
Hiroyuki Nakashima
Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
Manabu Kinoshita
Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
Hiroaki Kitagishi
Department of Molecular Chemistry and Biochemistry, Doshisha University, Kyotanabe, Kyoto, 610-0321, Japan
Yasuko Iwakiri
Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, 06510, United States
Yutaka Sasaki
Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Yasuhito Tanaka
Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Masaki Otagiri
Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, Kumamoto, Japan
Hiroshi Watanabe
Department of Clinical Pharmacy and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Corresponding author. Department of Clinical Pharmacy and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi Kumamoto, 862-0973, Japan.
Toru Maruyama
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Corresponding author. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Kumamoto, 862-0973, Japan.
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.