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Published on: September 9, 2021
Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice
Marije Boesjes1, Vincent W Bloks1, Jurre Hageman1
1Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Abstract:
The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.
Insights
The study reveals that two forms of the Farnesoid X Receptor (FXR), FXRα2 and FXRα4, differentially impact bile salt and lipoprotein metabolism. FXRα2 uniquely alters bile salt composition and increases sterol excretion.
Area of Science:
- Biochemistry
- Molecular Biology
- Metabolic Research
Background:
- The nuclear receptor FXR is a bile salt sensor regulating bile acid synthesis and transport in enterohepatic circulation.
- FXR also influences key metabolic pathways, with four known splice variants (FXRα1-4) exhibiting distinct expression and activity, though their physiological roles are unclear.
Purpose of the Study:
- To investigate the specific roles of hepatic FXRα2 and FXRα4 in modulating bile salt and lipoprotein metabolism.
- To elucidate the differential physiological relevance of FXR splice variants in vivo.
Main Methods:
- Stable expression of FXRα2 and FXRα4 in liver-specific, self-complementary adeno-associated viral vectors.
- Utilizing total body FXR knock-out mice to assess isoform-specific functions.
- Analysis of hepatic gene expression profiles, HDL levels, bile salt pool hydrophobicity, and sterol excretion.
Main Results:
- Both FXRα2 and FXRα4 largely normalized the hepatic gene expression profile in FXR knock-out mice.
- FXRα2 demonstrated greater efficacy in lowering elevated HDL levels and transrepressing Cyp8b1, a key regulator of cholate synthesis.
- FXRα2-transduced mice exhibited increased neutral sterol excretion compared to FXRα4-transduced mice, without impacting intestinal cholesterol absorption.
Conclusions:
- Hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.
- FXRα2 specifically influences bile salt hydrophobicity and enhances neutral sterol excretion, highlighting isoform-specific functions.
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