Bardoxolone methyl improves non-alcoholic steatohepatitis through
inhibition of macrophage infiltration.
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.