Inhibition of ileal bile acid transport lowers plasma cholesterol levels by inactivating hepatic farnesoid X receptor and stimulating cholesterol 7α-hydroxylase☆
Section snippets
Animal experiment
Male NZW (n = 18) rabbits weighing 2.5 to 3.0 kg (Convance, Denver, PA) were used in this study. The rabbits were divided into (1) controls (n = 10) and (2) fed SC-435 125 mg/kg/d for 1 week (n = 8). SC-435 was provided by Pharmacia Discovery Research (St Louis, MO) and was suspended in 20% Liposyn (Abbott Laboratories, North Chicago, IL) to make a concentration of 187.5 mg/mL. The average body weight of the rabbits was approximately 3 kg, such that 2 mL of 187.5 mg/mL SC-435 solution provided
Results
Fecal bile acid outputs measured by GLC increased 8.2 times (1.9 ± 1.5 to 17.0 ± 10.1 mg/d, P < .001) in rabbits treated with SC-435 for 1 week, reflecting substantial bile acid malabsorption (Fig 1A). However, there was no diarrhea found in the rabbits after the treatment with SC-435. Plasma cholesterol levels decreased 26%, from 34 ± 5 to 25 ± 5 mg/dL (P < .05) after treatment with SC-435 (Fig 1B). However, the bile acid pool size did not change significantly in rabbits treated with SC-435
Discussion
This study demonstrated that SC-435 is a potent inhibitor of ileal bile acid absorption in rabbits. After 1 week of treatment with SC-435, fecal bile acid outputs increased 8.3-fold. As a result, the flux of bile acids (activating ligands for FXR) returned to the liver diminished and hepatic FXR was inactivated. This change was indicated by reduced hepatic expression of 2 FXR target genes, SHP and BSEP, after treatment with SC-435. Since FXR is a powerful negative regulator of CYP7A1
Acknowledgements
We thank Bibiana Pcolinsky for her excellent technical support.
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Supported by VA Research Service, Washington DC, Grant No. DK 56830 from the National Institutes of Health, and a grant from Pharmacia Discovery Research, St Louis, MO.
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Current address for H.L.: Shanghai Institute of Digestive Disease, Department of Medicine, Ren Ji Hospital, Shanghai Second Medical University, Shanghai, P.R. China.