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-κB, 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.