Hexa Histidine-Tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species.

Autor: Dat NQ; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.; Department of Pediatrics, Hanoi Medical University, Hanoi, Vietnam., Thuy LTT; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Hieu VN; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Hai H; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Hoang DV; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Thi Thanh Hai N; Department of Biochemistry, Hanoi Medical University, Hanoi, Vietnam., Thuy TTV; Biological Resources Vinmec Tissue Bank, Vinmec Healthcare System, Hanoi, Vietnam., Komiya T; Department of Biology, Faculty of Science, Osaka City University, Osaka, Japan., Rombouts K; Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom., Dong MP; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Hanh NV; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Hoang TH; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Sato-Matsubara M; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Daikoku A; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Kadono C; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Oikawa D; Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan., Yoshizato K; Academic Advisor's Office, PhoenixBio Co., Ltd., Hiroshima, Japan.; Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan., Tokunaga F; Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan., Pinzani M; Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom., Kawada N; Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.; Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2021 Jun; Vol. 73 (6), pp. 2527-2545. Date of Electronic Publication: 2021 May 22.
DOI: 10.1002/hep.31752
Abstrakt: Background and Aims: Antifibrotic therapy remains an unmet medical need in human chronic liver disease. We report the antifibrotic properties of cytoglobin (CYGB), a respiratory protein expressed in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis.
Approach and Results: Cygb-deficient mice that had bile duct ligation-induced liver cholestasis or choline-deficient amino acid-defined diet-induced steatohepatitis significantly exacerbated liver damage, fibrosis, and reactive oxygen species (ROS) formation. All of these manifestations were attenuated in Cygb-overexpressing mice. We produced hexa histidine-tagged recombinant human CYGB (His-CYGB), traced its biodistribution, and assessed its function in HSCs or in mice with advanced liver cirrhosis using thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). In cultured HSCs, extracellular His-CYGB was endocytosed and accumulated in endosomes through a clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type 1 alpha 1 production and α-smooth muscle actin expression. Replacement the iron center of the heme group with cobalt nullified the effect of His-CYGB. In addition, His-CYGB induced interferon-β secretion by HSCs that partly contributed to its antifibrotic function. Momelotinib incompletely reversed the effect of His-CYGB. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis, and oxidative cell damage in mice administered TAA or DDC mice without adverse effects. RNA-sequencing analysis revealed the down-regulation of inflammation- and fibrosis-related genes and the up-regulation of antioxidant genes in both cell culture and liver tissues. The injected His-CYGB predominantly localized to HSCs but not to macrophages, suggesting specific targeting effects. His-CYGB exhibited no toxicity in chimeric mice with humanized livers.
Conclusions: His-CYGB could have antifibrotic clinical applications for human chronic liver diseases.
(© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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