Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression

doi:10.1016/S0016-5085(03)00896-5

Gastroenterology

Volume 125, Issue 2, August 2003, Pages 544-555

https://doi.org/10.1016/S0016-5085(03)00896-5 Get rights and content

Abstract

Background & aims:

Increased serum triglyceride levels constitute a risk factor for coronary heart disease. Apolipoprotein CIII (Apo CIII) is a determinant of serum triglyceride metabolism. In this study, we investigated whether activators of the nuclear farnesoid X receptor (FXR) modulate Apo CIII gene expression.

Methods:

The influence of bile acids and synthetic FXR activators on Apo CIII and triglyceride metabolism was studied in vivo by using FXR wild-type and FXR-deficient mice and in vitro by using human primary hepatocytes and HepG2 cells.

Results:

In mice, treatment with the FXR agonist taurocholic acid strongly decreased serum triglyceride levels, an effect associated with reduced Apo CIII serum and liver messenger RNA levels. By contrast, no change was observed in FXR-deficient mice. Incubation of human primary hepatocytes and HepG2 cells with bile acids or the nonsteroidal synthetic FXR agonist GW4064 resulted in a dose-dependent down-regulation of Apo CIII gene expression. Promoter transfection experiments and mutation analysis showed that bile acid-activated FXR decrease human Apo CIII promoter activity via a negative FXR response element located in the I₄ footprint between nucleotides −739 and −704. Chromatin immunoprecipitation experiments showed that bile acid treatment led to binding of FXR/retinoid X receptor heterodimers to and displacement of HNF4α from this site. Bile acid treatment still repressed liver Apo CIII gene expression in hepatic HNF4α-deficient mice, suggesting an active rather than a competitive mechanism of Apo CIII repression by the FXR.

Conclusions:

We identified bile acid and synthetic activators of the nuclear FXR as negative regulators of Apo CIII expression, an effect that may contribute to the triglyceride-decreasing action of FXR agonists.

Section snippets

Animals and treatment

FXR-deficient mice, obtained as described previously,34 were backcrossed for 5 generations in the C57BL/6 genetic background. Male C57BL/6 wild-type (IFFA-CREDO, L’Arbresle, France) and FXR-deficient mice were divided into 2 groups (n = 4 per group) of animals randomized on basal serum apo CIII levels. Liver-specific HNF4α-deficient mice and floxed control mice44 were divided into 2 groups (n = 3 per group). One group received a standard rodent chow diet (control), whereas the other group

Bile acid treatment reduces serum triglyceride and apolipoprotein CIII concentrations and liver apolipoprotein CIII messenger RNA levels in mice

To study whether apo CIII gene expression is regulated in vivo by BAs, wild-type mice were treated for 5 days with chow supplemented with 0.5% TCA (wt/wt) or not (control). Treatment did not influence body weight or food intake (data not shown). TCA treatment led to a significant decrease of serum triglyceride levels (Figure 1A). Furthermore, serum concentrations of apo CIII were reduced in TCA-treated animals (Figure 1B). To evaluate whether the reduction of serum apo CIII levels was

Discussion

Increased levels of serum triglycerides, especially when carried in atherogenic remnant lipoprotein particles, as occurs in individuals with metabolic syndromes and type 2 diabetes, constitute an independent risk factor for coronary heart disease.3, 4, 5 Apo CIII, a major determinant of intravascular triglyceride metabolism, has been identified as an independent risk factor and predictor of cardiovascular disease.20, 57 The identification of environmental and genetic factors controlling

Acknowledgements

The technical assistance of Lenaick Lemarca, Eric Baugé, and Frederic Percevault is greatly appreciated. The authors would like to acknowledge members of the B. Staels laboratory for helpful discussions. P. Young and T. Willson are thanked for providing various expression plasmids. Karine Bertrand and the Chemistry Department of Genfit SA are kindly acknowledged for providing the GW4064 compound.

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Citation Excerpt :
Several molecular mechanisms mediated this effect. First, the FXR/RXR heterodimer represses the expression of ApoC-III while inducing ApoC-II and ApoA-V thereby inducing the activity of lipoprotein lipase (LPL), a key enzyme involved in the lipolysis of VLDL and chylomicrons.276,277 Second, FXR induces the expression of the very-low-density lipoprotein cholesterol receptor (VLDL-R), an essential component in postprandial lipoprotein metabolism, by inducing LPL activity.
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^☆: Supported by grants from INSERM, Institut Pasteur de Lille, Genfit SA, the University of Lille II, the Leducq Foundation (B.S. and J.-C.F.), and the Fonds Européens de Development Regional (FEDER)-Conseil Regional Nord Pas-de-Calais (Génopole 01360124) and from the Fondation Lefoulon-Delalande, Institut de France (O.B.).

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Basic-liver, pancreas and biliary tractFarnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression☆

Abstract

Background & aims:

Methods:

Results:

Conclusions:

Section snippets

Animals and treatment

Bile acid treatment reduces serum triglyceride and apolipoprotein CIII concentrations and liver apolipoprotein CIII messenger RNA levels in mice

Discussion

Acknowledgements

Am J Cardiol

J Biol Chem

J Lipid Res

Metabolism

Lancet

J Lipid Res

J Lipid Res

Cell

Mol Cell

J Biol Chem

Mol Cell

Mol Cell

J Biol Chem

J Lipid Res

J Biol Chem

Cell

J Biol Chem

J Biol Chem

J Biol Chem

Anal Biochem

J Biol Chem

J Biol Chem

Cell

J Biol Chem

Hepatology

J Biol Chem

J Lipid Res

J Lipid Res

J Biol Chem

J Biol Chem

Genomics

Biochem Biophys Res Commun

Dev Cell

Dev Cell

Index of coronary artery atherogenesis

Mod Med

Basic-liver, pancreas and biliary tract
Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression☆