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Bardoxolone methyl improves non-alcoholic steatohepatitis through inhibition of macrophage infiltration.
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  • Kazuhiro Onuma,
  • Kenji Watanabe,
  • Keishiro Isayama,
  • Sayaka Ogi,
  • Yasunori Tokunaga,
  • Yoichi Mizukami
Kazuhiro Onuma
Yamaguchi University
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Kenji Watanabe
Yamaguchi University
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Keishiro Isayama
Yamaguchi University
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Sayaka Ogi
UBE Corporation
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Yasunori Tokunaga
UBE Corporation
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Yoichi Mizukami
Yamaguchi University

Corresponding Author:[email protected]

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Abstract

Background and purpose: Bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor (Nrf)2, which induces anti-oxidative-associated genes. CDDO-Me is known to exert protective effects against chronic inflammatory diseases in the kidney and lungs. However, its pharmacological effects on non-alcoholic steatohepatitis (NASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO-Me in a diet-induced NASH mouse model, and elucidated its pharmacological mechanisms using RNA-seq analysis. Experimental approach: CDDO-Me was orally administered to mice fed a choline-deficient, L-amino acid-defined, high-fat diet, and histological, biochemical, and transcriptome analyses were performed on the livers of mice that developed NASH. Key results: CDDO-Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly improved the symptoms of NASH. Whole-transcriptome analysis revealed that CDDO-Me inhibited the inflammatory pathway that leads to phagocyte recruitment, in addition to activating the Nrf2-dependent pathway. Among inflammatory pathways, CC chemokine ligand (CCL)3 and CCL4 in the downstream of NF-B, which are associated with the recruitment of macrophages expressing CC chemokine receptor (CCR)1 and CCR5, were released into blood in NASH mice. In contrast, CDDO-Me directly inhibited the expression of CCL3-CCR1 and CCL4-CCR5 in macrophages. Conclusions and Implications: Overall, this study revealed the potent hepatoprotective effect of CDDO-Me in a NASH mouse model, and demonstrated that its pharmacological effects were closely associated with the reduction of macrophage infiltration through CCL3-CCR1 and CCL4-CCR5 inhibition, in addition to Nrf2-mediated hepatoprotective effects.
18 Oct 2023Submitted to British Journal of Pharmacology
24 Oct 2023Assigned to Editor
24 Oct 2023Submission Checks Completed
24 Oct 2023Review(s) Completed, Editorial Evaluation Pending
27 Oct 2023Reviewer(s) Assigned