Effects of ablation and activation of Nrf2 on bile acid homeostasis in male mice.
The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in bile acid (BA) homeostasis remains controversial. In this study, activation of Nrf2 was achieved either pharmacologically by CDDO-imidazolide (CDDO-Im) or genetically through a "gene dose-response" model consisting of Nrf2-null, wild-type (WT), Keap1-knockdown (Keap1-KD), and Keap1-hepatocyte knockout (Keap1-HKO) mice. In WT mice, CDDO-Im increased bile flow and decreased hepatic BAs, which was associated with a down-regulation of the canalicular BA efflux transporter Bsep and an increase in biliary BA excretion. In contrast, hepatic Bsep and biliary BA excretion were not altered in Keap1-KD or Keap1-HKO mice, suggesting that Nrf2 is not important for regulating Bsep or BA-dependent bile flow. In contrast, hepatic Mrp2 and Mrp3 were up-regulated by both pharmacological and genetic activations of Nrf2. Furthermore, ileal BA transporters (Asbt and Ostβ) and cholesterol transporters (Abcg5 and Abcg8) were down-regulated by both pharmacological and genetic activations of Nrf2, suggesting a role of Nrf2 in intestinal absorption of BAs and cholesterol. In Nrf2-null mice, CDDO-Im down-regulated hepatic BA uptake transporters (Ntcp, Oatp1a1, and Oatp1b2), leading to a 39-fold increase of serum BAs. To conclude, the present study demonstrates that activation of Nrf2 in mice up-regulates Mrp2 and Mrp3 in the liver and down-regulates BA and cholesterol transporters in the intestine.
Toxicology and applied pharmacology
Bile Acid; Bile Acid Signaling; CDDO-Im; Nrf2
Zhang, Y., Lickteig, A. J., Liu, J., Csanaky, I., Klaassen, C. D. Effects of ablation and activation of Nrf2 on bile acid homeostasis in male mice. Toxicology and applied pharmacology 403, 115170-115170 (2020).