Alteration of the expression of adenosine triphosphate-binding cassette transporters associated with bile acid and cholesterol transport in the rat liver and intestine during cholestasis


Dr Toshinori Kamisako, Department of Hygiene, Kinki University School of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511, Japan. Email:


Background and Aim:  Multidrug resistance protein 2 (Mrp2), Mrp3, adenosine triphosphate-binding cassette transporter g5 (Abcg5) and adenosine triphosphate-binding cassette transporter g8 (Abcg8) have been identified as bile acid or cholesterol transporter in the enterocytes as well as hepatocytes. The purpose of the present study was to evaluate intestinal and hepatic adenosine triphosphate-binding cassette transporter expressions during cholestasis.

Methods:  Experiment 1: Rats were subjected to bile duct ligation or sham operation. Blood, liver and small intestines were obtained 24 and 72 h after operation. Experiment 2: Rats were divided into four groups as follows: (i) control group; (ii) diosgenin group (fed with diosgenin in diet [1%(wt/wt)] for 7 days); (iii) ethinyl estradiol group (recieved ethinyl estradiol [5 mg/kg daily] for 5 days); and (iv) diosgenin-ethinyl estradiol group (received ethinyl estradiol and diosgenin). After treatment, blood, bile, liver and intestines were obtained. The mRNA related to lipid and bile acid metabolism was analyzed by reverse transcription polymerase chain reaction.

Results:  Intestinal Mrp2 and Abcg5/Abcg8 mRNA expression remarkably decreased 24 h after bile duct ligation (43% and 61%/54% of sham operation) and recovered 72 h after bile duct ligation (103% and 95%/83% of sham operation). Intestinal Mrp3 mRNA expression did not change after bile duct ligation. Intestinal Mrp2 mRNA expression was remarkably increased in diosgenin and diosgenin-ethinyl estradiol groups in comparison with the control group. There were no significant differences in intestinal Mrp3 mRNA expression among the four groups. Hepatic Mrp3 mRNA expression was remarkably increased in the D, EE and DE groups in comparison with the control group (531%, 321% and 1160% of control, respectively, P < 0.01). Hepatic Abcg5 and Abcg8 mRNA expression decreased in ethinyl estradiol and diosgenin-ethinyl estradiol groups compared with the control group and there were no differences in intestinal Abcg5 and Abcg8 mRNA expressions among the four groups.

Conclusion:  Bile duct ligation affects not only hepatic but also the intestinal Mrp2 and Abcg5 and Abcg8 expressions. Intestinal Mrp2 mRNA level was regulated by factor in the lumen (e.g. diosgenin feeding). Cholestasis by ethinyl estradiol treatment was enhanced by diosgenin and the increase in hepatic Mrp3 mRNA level might affect the enhancement.

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