Elsevier

Metabolism

Volume 53, Issue 7, July 2004, Pages 927-932
Metabolism

Inhibition of ileal bile acid transport lowers plasma cholesterol levels by inactivating hepatic farnesoid X receptor and stimulating cholesterol 7α-hydroxylase

https://doi.org/10.1016/j.metabol.2004.01.017Get rights and content

Abstract

We investigated the effect of SC-435, a competitive inhibitor of ileal apical sodium-dependent bile acid cotransporter (ASBT) on ileal bile acid absorption and the hepatic nuclear receptor FXR (farnesoid X receptor), which regulates cholesterol 7α-hydroxylase (CYP7A1) activity and mRNA levels. Eighteen New Zealand White (NZW) rabbits were divided into 2 groups: controls (n = 10) and fed SC-435 125 mg/kg/d for 1 week (n = 8). In rabbits treated with SC-435, fecal bile acid outputs increased by more than 8 times, reflecting substantial bile acid malabsorption. Plasma cholesterol levels decreased 26%, while bile acid pool sizes and biliary bile acid outputs did not change after treatment. CYP7A1 activity increased 64% and mRNA rose by 4 times after treatment. The expression of FXR target genes in the liver, short heterodimer partner (SHP) and bile salt export pump (BSEP), decreased 11.6 and 2.6 times, respectively, after treatment, which indicates inactivation of hepatic FXR. However, the mRNA levels of ileal bile acid binding protein (IBABP) did not change significantly, while ileal ASBT mRNA expression increased by 2.4 times after treatment. Rabbits treated with SC-435 developed ileal bile acid malabsorption, which decreased the return of bile acids (FXR ligands) to the liver to inactivate hepatic FXR, which upregulated CYP7A1 and lowered plasma cholesterol levels. Although fecal bile acid malabsorption was substantial, increased bile acid production from hepatic cholesterol kept biliary bile acid outputs intact. Thus, a new balance was reached in the liver, where increased bile acid synthesis compensated for diminished ileal bile acid absorption to maintain the circulating enterohepatic bile acid pool.

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.

References (31)

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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.

1

Current address for H.L.: Shanghai Institute of Digestive Disease, Department of Medicine, Ren Ji Hospital, Shanghai Second Medical University, Shanghai, P.R. China.

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