Bile acid-induced elevated oxidative stress in the absence of farnesoid X receptor.
The major function of farnesoid X receptor (FXR) is to maintain bile acid and lipid homeostasis. Fxr-null mice, in which the levels of hepatic bile acid and lipid have been elevated, develop spontaneous liver tumors. We evaluated differences in hepatic bile acid and triglyceride concentrations, and in generation of oxidative stress between wild-type mice and Fxr-null mice. The hepatic levels of 8-hydroxy-2'-deoxyguanosine (8OHdG), thiobarbituric acid-reactive substance (TBARS) and hydroperoxides, oxidative stress-related genes, and nuclear factor (erythroid-2 like) factor 2 (Nrf2) protein in Fxr-null mice were significantly higher than those in wild-type mice. An increase in the hepatic bile acid concentration in Fxr-null mice fed a cholic acid (CA) diet resulted in an increase in the hepatic levels of hydroperoxides, TBARS and 8OHdG, whereas a decrease in the hepatic concentration in mice fed a diet containing ME3738 (22beta-methoxyolean-12-ene-3beta,24(4beta)-diol) resulted in a decrease in these oxidative stress marker levels. A good correlation was observed between the hepatic bile acid concentrations and the hepatic oxidative stress marker levels, although there was no significant correlation between the hepatic triglyceride concentrations and oxidative stress. The results show that oxidative stress is spontaneously enhanced in Fxr-null mice, which may be attributable to a continuously high level of hepatic bile acids.
Nomoto
Masahiro
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Miyata
Masaaki
M
Yin
Shanai
S
Kurata
Yasushi
Y
Shimada
Miki
M
Yoshinari
Kouichi
K
Gonzalez
Frank J
FJ
Suzuki
Kokichi
K
Shibasaki
Shigeki
S
Kurosawa
Tohru
T
Yamazoe
Yasushi
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016707:Tissue Fixation; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D003849:Deoxyguanosine; D006657:Histones; D006861:Hydrogen Peroxide; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D017392:Thiobarbituric Acid Reactive Substances; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C477463:ME3738; C495636:Nfe2l2 protein, mouse