TY - JOUR
T1 - ME3738 protects against lithocholic acid-induced hepatotoxicity, which is associated with enhancement of biliary bile acid and cholesterol output
AU - Nomoto, Masahiro
AU - Miyata, Masaaki
AU - Shimada, Miki
AU - Yoshinari, Kouichi
AU - Gonzalez, Frank J.
AU - Shibasaki, Shigeki
AU - Kurosawa, Tohru
AU - Shindo, Yasuhiro
AU - Yamazoe, Yasushi
N1 - Funding Information:
We would like to express our sincere thanks to Dr. Tsutomu Matsubara, Dr. Kiyoshi Nagata, Ms. Mariko Takagi and Dr. Shoji Nishiyama for skillful technical advice and support. This study was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan and by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, Japan.
PY - 2007/11/28
Y1 - 2007/11/28
N2 - ME3738 (22β-methoxyolean-12-ene-3β, 24(4β)-diol), a derivative of soyasapogenol, attenuates liver disease in several models of chronic liver inflammation. In the present study, we have investigated a protective effect of ME3738 in a typical bile acid-induced cholestatic liver model, lithocholate (LCA) feeding mouse. Co-administration of ME3738 resulted in decreases in plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities and hepatic bile acid level, and increases in biliary outputs of bile acid and cholesterol, as compared with the results in mice treated with LCA alone. LCA sulfation by hydroxysteroid sulfotransferase 2a and hydroxylation have been reported to be involved in protection against LCA-induced hepatotoxicity. ME3738-treatment, however, had no clear influence on the hydroxysteroid sulfotransferase 2a protein level and LCA 6α-, 6β- and 7α-hydroxylase activities, but increased biliary cholesterol output. Cholate (CA)-treatment has been shown to induce hepatotoxicity in farnesoid X receptor-null mice, which is scarcely dependent on bile acid sulfation and hydroxylation but associated with decreased biliary bile acid output. Co-administration of ME3738 decreased the ALT and ALP activities and hepatic bile acid level, and increased biliary outputs of bile acid and cholesterol in farnesoid X receptor-null mice, as compared with the results in the mice treated with CA. Moreover, a clear correlation between biliary outputs of cholesterol and bile acid was observed in these two bile acid-induced hepatotoxicity mouse models. These results suggest that ME3738 protects against bile acid-induced hepatotoxicity through increased biliary bile acid output that is not related to bile acid metabolism but associated with cholesterol output.
AB - ME3738 (22β-methoxyolean-12-ene-3β, 24(4β)-diol), a derivative of soyasapogenol, attenuates liver disease in several models of chronic liver inflammation. In the present study, we have investigated a protective effect of ME3738 in a typical bile acid-induced cholestatic liver model, lithocholate (LCA) feeding mouse. Co-administration of ME3738 resulted in decreases in plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities and hepatic bile acid level, and increases in biliary outputs of bile acid and cholesterol, as compared with the results in mice treated with LCA alone. LCA sulfation by hydroxysteroid sulfotransferase 2a and hydroxylation have been reported to be involved in protection against LCA-induced hepatotoxicity. ME3738-treatment, however, had no clear influence on the hydroxysteroid sulfotransferase 2a protein level and LCA 6α-, 6β- and 7α-hydroxylase activities, but increased biliary cholesterol output. Cholate (CA)-treatment has been shown to induce hepatotoxicity in farnesoid X receptor-null mice, which is scarcely dependent on bile acid sulfation and hydroxylation but associated with decreased biliary bile acid output. Co-administration of ME3738 decreased the ALT and ALP activities and hepatic bile acid level, and increased biliary outputs of bile acid and cholesterol in farnesoid X receptor-null mice, as compared with the results in the mice treated with CA. Moreover, a clear correlation between biliary outputs of cholesterol and bile acid was observed in these two bile acid-induced hepatotoxicity mouse models. These results suggest that ME3738 protects against bile acid-induced hepatotoxicity through increased biliary bile acid output that is not related to bile acid metabolism but associated with cholesterol output.
KW - ATP-binding cassette g5/8 (Abcg5/8)
KW - Abcb11)
KW - Bile salt export pump (Bsep
KW - Cholesterol
KW - Farnesoid X receptor (Fxr)
KW - Lithocholic acid
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U2 - 10.1016/j.ejphar.2007.07.004
DO - 10.1016/j.ejphar.2007.07.004
M3 - Article
C2 - 17651726
AN - SCOPUS:35348821196
VL - 574
SP - 192
EP - 200
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 2-3
ER -