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Nuclear Receptor Control of Enterohepatic Circulation

Frank J. Gonzalez

10.1002/cphy.c120007

Source: Volume 2, Issue 4, October 2012

Published online: October 2012

Full Article on Wiley Online Library



Abstract

Enterohepatic circulation is responsible for the capture of bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Bile acids are secreted from the liver in the form of mixed micelles that also contain phosphatidylcholines and cholesterol that facilitate the uptake of fats and vitamins from the diet due to the surfactant properties of bile acids and lipids. Bile acids are synthesized in the liver from cholesterol by a cascade of enzymes that carry out oxidation and conjugation reactions, and transported to the bile duct and gall bladder where they are stored before being released into the intestine. Bile flow from the gall bladder to the small intestine is triggered by food intake in accordance with its role in lipid and vitamin absorption from the diet. Bile acids are further metabolized by gut bacteria and are transported back to the circulation. Metabolites produced in the liver are termed primary bile acids or primary conjugated bile salts, while the metabolites generated by bacterial are called secondary bile acids. About 95% of bile acids are reabsorbed in the proximal and distal ileum into the hepatic portal vein and then into the liver sinusoids, where they are efficiently transported into the liver with little remaining in circulation. Each bile acid is reabsorbed about 20 times on average before being eliminated. Enterohepatic circulation is under tight regulation by nuclear receptor signaling, notably by the farnesoid X receptor (FXR). Published 2012. Compr Physiol 2:2811‐2828, 2012.

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Figure 1. Figure 1.

Enterohepatic circulation of bile acids. Bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Coincident with bile acid recirculation is the removal and reuptake of drugs, usually conjugated high Mr drugs. Cholesterol is the substrate for bile acid synthesis, one of the routes for mammalian disposal of cholesterol. The author thanks Tsutomu Matsubara for help in preparing this figure.
Figure 2. Figure 2.

Pathway for the synthesis of bile acids. Neutral pathway: cholesterol is converted to 7α‐hydroxycholesterol (I) by CYP7A1, the rate‐limiting enzyme in cholesterol degradation in the major neutral pathway of bile acid synthesis. 7α‐Hydroxycholesterol is reduced to 7α‐hydroxy‐4‐cholesten‐3‐one (II), which is metabolized to 7α,12,‐dihydroxy‐4‐cholesten‐3‐one (III) by CYP12A1 or reduced to 5β‐cholestane‐3α,7α‐diol (VII). 7α,12,‐Dihydroxy‐4‐cholesten‐3‐one is oxidized to 5β‐cholestane‐3α,7α,12,‐triol (IV), and 5β‐cholestane‐3α,7α‐diol is oxidized by CYP27A1 to 3α,7α‐dihydroxy‐5β‐cholestanoic acid (VIII), which is then metabolized to the terminal metabolite chenodeoxycholic acid (IX) through a demethylation reaction. 5β‐Cholestane‐3α,7α,12,‐triol is also oxidized to 3α,7α,12,‐trihydroxy‐5β‐cholestanoic acid (V) by CYP27A1, which is converted to the terminal metabolite cholic acid (VI) by a demethylation reaction. Acidic pathway: cholesterol is also converted to 27‐hydroxycholesterol (X) and 3β‐hydroxy‐5‐cholestenoic acid (XI) by CYP27A1 in the minor acidic pathway. 3β‐Hydroxy‐5‐cholestenoic acid is metabolized to 3β,7α‐hydroxy‐5‐cholestenoic acid (XII) by CYP7B1. A series of reactions converts 3β,7α‐hydroxy‐5‐cholestenoic acid to chenodeoxycholic acid (IX). The author thanks Fei Li for making this figure.
Figure 3. Figure 3.

Domain structure of nuclear receptors. The nuclear receptor superfamily proteins have several functional domains; the activation function 1 (AF1) domain at the N terminus, the DNA‐binding domain (DBD), a hinge region, a ligand‐binding domain (LBD) and another activation function 2 (AF2) domain at the C terminus. The small heterodimer protein (SHP) that has a major role in the regulation of genes involved in bile acid synthesis and transport, lacks the AF1 and DBD domains. Derived in part, with permission, from Science Slides (scienceslides.com).
Figure 4. Figure 4.

Nuclear receptor control of gene expression. Nuclear receptors (NR) bind to cis‐acting elements usually located upstream of target genes. In the case of those receptors involved in metabolic control that bind as heterodimers with the retinoid X receptor, the binding site is composed of a direct repeat element (DR) separated by 1 to 4 nucleotides. In the absence of ligand, the NR is either unbound or bound to DNA. If bound to DNA in the absence of ligand, the receptor is complexed to a corepressor and histone deacetylases (HDAC) or demethylases, enzymes that remove acetyl or methyl groups from histones, which serve to keep the chromatin compact. In the presence of ligands, the corepressor is released and coactivators bind along with histone acetyltransferases and histone methyltransferases and components of the RNA polymerase (RNAP) complex resulting in gene transcription. Derived in part, with permission, from Science Slides (scienceslides.com).
Figure 5. Figure 5.

Repression of the Cyp7a1 gene by small heterodimer protein (SHP). Farnesoid X receptor (FXR) activates expression of SHP in the presence of bile acids agonist. SHP then binds to the positive regulator liver receptor homolog 1 (LRH‐1) and inhibits its transactivation of Cyp7a1 and other target genes such as Asbt. Derived in part, with permission, from Science Slides (scienceslides.com) and reference 76.
Figure 6. Figure 6.

Mechanism for gene suppression by Rev‐erbα. Rev‐erbα binds heme and represses gene transcription by recruitment of NCoR‐HDAC3 corepressor complex and promotes chromatin condensation. Rev‐erbα suppresses expression of Cyp7a1 and the positive clock component, Bmal1 that controls circadian rhythm. Derived in part, with permission, from Science Slides (scienceslides.com) and reference 160.
Figure 7. Figure 7.

Mechanism for the enterohepatic circulation of bile acids. Bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Coincident with bile acid recirculation is the removal and reuptake of drugs, usually conjugated high Mr drugs. Cholesterol is the substrate for bile acid synthesis, one of the routes for mammalian disposal of cholesterol. The author thanks Tsutomu Matsubara for help in preparing this figure.


Figure 1.

Enterohepatic circulation of bile acids. Bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Coincident with bile acid recirculation is the removal and reuptake of drugs, usually conjugated high Mr drugs. Cholesterol is the substrate for bile acid synthesis, one of the routes for mammalian disposal of cholesterol. The author thanks Tsutomu Matsubara for help in preparing this figure.



Figure 2.

Pathway for the synthesis of bile acids. Neutral pathway: cholesterol is converted to 7α‐hydroxycholesterol (I) by CYP7A1, the rate‐limiting enzyme in cholesterol degradation in the major neutral pathway of bile acid synthesis. 7α‐Hydroxycholesterol is reduced to 7α‐hydroxy‐4‐cholesten‐3‐one (II), which is metabolized to 7α,12,‐dihydroxy‐4‐cholesten‐3‐one (III) by CYP12A1 or reduced to 5β‐cholestane‐3α,7α‐diol (VII). 7α,12,‐Dihydroxy‐4‐cholesten‐3‐one is oxidized to 5β‐cholestane‐3α,7α,12,‐triol (IV), and 5β‐cholestane‐3α,7α‐diol is oxidized by CYP27A1 to 3α,7α‐dihydroxy‐5β‐cholestanoic acid (VIII), which is then metabolized to the terminal metabolite chenodeoxycholic acid (IX) through a demethylation reaction. 5β‐Cholestane‐3α,7α,12,‐triol is also oxidized to 3α,7α,12,‐trihydroxy‐5β‐cholestanoic acid (V) by CYP27A1, which is converted to the terminal metabolite cholic acid (VI) by a demethylation reaction. Acidic pathway: cholesterol is also converted to 27‐hydroxycholesterol (X) and 3β‐hydroxy‐5‐cholestenoic acid (XI) by CYP27A1 in the minor acidic pathway. 3β‐Hydroxy‐5‐cholestenoic acid is metabolized to 3β,7α‐hydroxy‐5‐cholestenoic acid (XII) by CYP7B1. A series of reactions converts 3β,7α‐hydroxy‐5‐cholestenoic acid to chenodeoxycholic acid (IX). The author thanks Fei Li for making this figure.



Figure 3.

Domain structure of nuclear receptors. The nuclear receptor superfamily proteins have several functional domains; the activation function 1 (AF1) domain at the N terminus, the DNA‐binding domain (DBD), a hinge region, a ligand‐binding domain (LBD) and another activation function 2 (AF2) domain at the C terminus. The small heterodimer protein (SHP) that has a major role in the regulation of genes involved in bile acid synthesis and transport, lacks the AF1 and DBD domains. Derived in part, with permission, from Science Slides (scienceslides.com).



Figure 4.

Nuclear receptor control of gene expression. Nuclear receptors (NR) bind to cis‐acting elements usually located upstream of target genes. In the case of those receptors involved in metabolic control that bind as heterodimers with the retinoid X receptor, the binding site is composed of a direct repeat element (DR) separated by 1 to 4 nucleotides. In the absence of ligand, the NR is either unbound or bound to DNA. If bound to DNA in the absence of ligand, the receptor is complexed to a corepressor and histone deacetylases (HDAC) or demethylases, enzymes that remove acetyl or methyl groups from histones, which serve to keep the chromatin compact. In the presence of ligands, the corepressor is released and coactivators bind along with histone acetyltransferases and histone methyltransferases and components of the RNA polymerase (RNAP) complex resulting in gene transcription. Derived in part, with permission, from Science Slides (scienceslides.com).



Figure 5.

Repression of the Cyp7a1 gene by small heterodimer protein (SHP). Farnesoid X receptor (FXR) activates expression of SHP in the presence of bile acids agonist. SHP then binds to the positive regulator liver receptor homolog 1 (LRH‐1) and inhibits its transactivation of Cyp7a1 and other target genes such as Asbt. Derived in part, with permission, from Science Slides (scienceslides.com) and reference 76.



Figure 6.

Mechanism for gene suppression by Rev‐erbα. Rev‐erbα binds heme and represses gene transcription by recruitment of NCoR‐HDAC3 corepressor complex and promotes chromatin condensation. Rev‐erbα suppresses expression of Cyp7a1 and the positive clock component, Bmal1 that controls circadian rhythm. Derived in part, with permission, from Science Slides (scienceslides.com) and reference 160.



Figure 7.

Mechanism for the enterohepatic circulation of bile acids. Bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Coincident with bile acid recirculation is the removal and reuptake of drugs, usually conjugated high Mr drugs. Cholesterol is the substrate for bile acid synthesis, one of the routes for mammalian disposal of cholesterol. The author thanks Tsutomu Matsubara for help in preparing this figure.

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Article Title: Nuclear Receptor Control of Enterohepatic Circulation
 

How to Cite

Frank J. Gonzalez. Nuclear Receptor Control of Enterohepatic Circulation. Compr Physiol 2012, 2: 2811-2828. doi: 10.1002/cphy.c120007