Institute of Gene Research, Yamaguchi University Science Research Center, Yamaguchi, Japan.
Pharmaceutical Research Laboratory, Pharmaceutical Division, UBE Corporation, Yamaguchi, Japan.
Br J Pharmacol. 2024 Aug;181(15):2545-2565. doi: 10.1111/bph.16374. Epub 2024 Apr 10.
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 2 (Nrf2), which induces the expression of antioxidative-associated genes. CDDO-Me exerts protective effects against chronic inflammatory diseases in the kidneys and lungs. However, its pharmacological effects on metabolic dysfunction-associated steatohepatitis (MASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO-Me in a diet-induced MASH mouse model and elucidated its pharmacological mechanisms using RNA-seq analysis.
CDDO-Me was orally administered to mice fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), and histological, biochemical, and transcriptomic analyses were performed on livers of mice that developed MASH.
CDDO-Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly prevented the symptoms of MASH. Whole-transcriptome analysis revealed that CDDO-Me inhibited the inflammatory pathway that led to phagocyte recruitment, in addition to activating the Nrf2-dependent pathway. Among inflammatory pathways, CC chemokine ligands (CCL)3 and CCL4, which are downstream of NF-κB and are associated with the recruitment of macrophages expressing CC chemokine receptors (CCR)1 and CCR5, were released into the blood in MASH mice. However, CDDO-Me directly inhibited the expression of CCL3-CCR1 and CCL4-CCR5 in macrophages.
Overall, we revealed the potent hepatoprotective effect of CDDO-Me in a MASH mouse model and demonstrated that its pharmacological effects were closely associated with a reduction of macrophage infiltration, through CCL3-CCR1 and CCL4-CCR5 inhibition, in addition to Nrf2-mediated hepatoprotective effects.
Bardoxolone 甲酯（2-氰基-3,12-二氧代-1,9(11)-二烯-28-酸甲酯，CDDO-Me）是核因子红细胞 2 相关因子 2（Nrf2）的有效激活剂，可诱导抗氧化相关基因的表达。CDDO-Me 对肾脏和肺部的慢性炎症性疾病具有保护作用。然而，其在由脂肪堆积引起的代谢功能障碍相关脂肪性肝炎（MASH）中的药理作用尚不清楚。在本研究中，我们在饮食诱导的 MASH 小鼠模型中研究了 CDDO-Me 的肝保护作用，并通过 RNA-seq 分析阐明了其药理机制。
CDDO-Me 通过口服给予喂食胆碱缺乏、L-氨基酸定义的高脂肪饮食（CDAHFD）的小鼠，并对发生 MASH 的小鼠的肝脏进行组织学、生化和转录组学分析。
CDDO-Me 给药诱导了 Nrf2 下游抗氧化基因和胆固醇转运蛋白的表达，并显著预防了 MASH 的症状。全转录组分析显示，CDDO-Me 抑制了导致吞噬细胞募集的炎症途径，同时激活了 Nrf2 依赖性途径。在炎症途径中，CC 趋化因子配体（CCL）3 和 CCL4，它们是 NF-κB 的下游产物，与表达 CC 趋化因子受体（CCR）1 和 CCR5 的巨噬细胞的募集有关，在 MASH 小鼠的血液中释放。然而，CDDO-Me 直接抑制了巨噬细胞中 CCL3-CCR1 和 CCL4-CCR5 的表达。
总的来说，我们在 MASH 小鼠模型中揭示了 CDDO-Me 的强大肝保护作用，并证明其药理作用与巨噬细胞浸润的减少密切相关，这是通过 CCL3-CCR1 和 CCL4-CCR5 的抑制以及 Nrf2 介导的肝保护作用实现的。
