Oral administration of oleanolic acid, isolated from Swertia mussotii Franch, attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.
OBJECTIVE
Oleanolic acid is abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb for the treatment of jaundice. However, the hepatoprotective role of oleanolic acid in obstructive cholestasis and its underlying molecular mechanism are unclear.


METHODS
Normal rats and bile duct-ligated (BDL) rats were given oleanolic acid and serum biochemistry, bile salts, and pro-inflammatory factors were measured, as well as the expression levels of liver bile acid synthesis and detoxification enzymes, membrane transporters, nuclear receptors, and transcriptional factors.


RESULTS
Oral administration of oleanolic acid at 100 mg/kg did not cause rat liver injury. However, it significantly reduced the serum levels of alanine aminotransferase (ALT) on days 7 and 14, aspartate aminotransferase (AST) and TNF-α on day 14, and alkaline phosphatase (ALP) and IL-1β on days 3, 7, and 14 in the BDL rats. Furthermore, the serum levels of total bile acid (TBA) and bile acids, including CDCA, CA, DCA, and Tα/βMCA were significantly reduced by oleanolic acid on day 3 in the BDL rats. In addition, the expression levels of detoxification enzymes Cyp3a, Ugt2b, Sult2a1, Gsta1-2, and Gstm1-3, membrane transporters Mrp3, Mrp4, Ostβ, Mdr1, Mdr2, and Bsep, nuclear receptors Pxr, Vdr, Hnf4α, Rxrα, Rarα, Lxr, and Lrh-1, and transcriptional factors Nrf2, Hnf3β, and Ahr were significantly increased in oleanolic acid-treated rats.


CONCLUSIONS
We demonstrated that the oral administration of oleanolic acid attenuates liver injury, inflammation, and cholestasis in BDL rats. The anti-cholestatic effect may be associated with the induction of hepatic detoxification enzymes and efflux transporters mediated by nuclear receptors and transcriptional factors.
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Jin
J
Chai
Department of Traditional Chinese Medicine; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Xiaohuang
X
Du
Department of Pediatrics, Southwest Hospital; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Sheng
S
Chen
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
XinChan
X
Feng
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Ying
Y
Cheng
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Liangjun
L
Zhang
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Yu
Y
Gao
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Shaoxue
S
Li
Department of School of Nursing; College of Pharmacy, Third Military Medical University Chongqing 400038, P.R. China.
Xiaochong
X
He
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Rongquan
R
Wang
Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University Chongqing 400038, P.R. China.
Xiangdong
X
Zhou
Chongqing Academy of Chinese Material Medical Chongqing 400065, P.R. China.
Yong
Y
Yang
Chongqing Academy of Chinese Material Medical Chongqing 400065, P.R. China.
Weizao
W
Luo
Department of Gastroenterology; Southwest Hospital, College of Pharmacy, Third Military Medical University Chongqing 400038.
Wensheng
W
Chen
Oleanolic acid; detoxification enzyme; hepatic efflux transporter; nuclear receptor; obstructive cholestasis; synthetic enzyme; transcriptional factor