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Cited by 196Drug Transport and Resistance MechanismsFibroblast Growth Factor ResearchCholesterol and Lipid Metabolism

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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

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Katafuchi, Takeshi, Makishima, Makoto·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23116046PMC PMC9181207
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Abstract

Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

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Figure 1 BA biosynthesis pathways in humans and mice. The classic bile acid biosynthesis pathway begins with converting cholesterol to 7α-hydroxycholesterol by CYP7A1 and subsequent conversion to C4. C4 is then converted to CA or CDCA by multiple enzymes including CYP8B1 and CYP27A1. CA and CDCA are then conjugated with taurine (t-) or glycine (g-) by BACS and BAAT. In mice, CDCA is further converted to α-MCA, then β-MCA by CYP2C70, which is not present in humans. Alternative pathways are initiated by CYP27A1 in the liver, macrophages, and the adrenal gland, cholesterol 25-hydroxylase (CH25H) in the liver and CYP46A1 in the brain. Products of the first two pathways are further converted by CYP7B1 to different steroidal compounds to produce BAs, oxysterols, and steroid hormones. The last pathway is involved in regulating cholesterol levels in the brain and the final product by CYP39A1 is delivered to the liver for BA synthesis. Red boxes indicate enzymes and BAs in both humans and mice, blue boxes indicate BAs mainly in humans, and green boxes indicate enzymes and BAs existing only in mice.
Figure 1 BA biosynthesis pathways in humans and mice. The classic bile acid biosynthesis pathway begins with converting cholesterol to 7α-hydroxycholesterol by CYP7A1 and subsequent conversion to C4. C4 is then converted to CA or CDCA by multiple enzymes including CYP8B1 and CYP27A1. CA and CDCA are then conjugated with taurine (t-) or glycine (g-) by BACS and BAAT. In mice, CDCA is further converted to α-MCA, then β-MCA by CYP2C70, which is not present in humans. Alternative pathways are initiated by CYP27A1 in the liver, macrophages, and the adrenal gland, cholesterol 25-hydroxylase (CH25H) in the liver and CYP46A1 in the brain. Products of the first two pathways are further converted by CYP7B1 to different steroidal compounds to produce BAs, oxysterols, and steroid hormones. The last pathway is involved in regulating cholesterol levels in the brain and the final product by CYP39A1 is delivered to the liver for BA synthesis. Red boxes indicate enzymes and BAs in both humans and mice, blue boxes indicate BAs mainly in humans, and green boxes indicate enzymes and BAs existing only in mice.CC BY · PubMed Central
Figure 2 Secondary BA biosynthesis. Primary BAs are initially deconjugated by BSH, which is encoded by most gut microbiota. Deconjugated CDCA is then converted to UDCA and by 7α- and 7β-HSDH expressed in different bacteria or LCA by multiple steps of catalytic reactions by Bai enzymes in Clostridium spp. Deconjugated CA is also converted to UCA by 7α- and 7β-HSDH or DCA by Bai enzymes.
Figure 2 Secondary BA biosynthesis. Primary BAs are initially deconjugated by BSH, which is encoded by most gut microbiota. Deconjugated CDCA is then converted to UDCA and by 7α- and 7β-HSDH expressed in different bacteria or LCA by multiple steps of catalytic reactions by Bai enzymes in Clostridium spp. Deconjugated CA is also converted to UCA by 7α- and 7β-HSDH or DCA by Bai enzymes.CC BY · PubMed Central
Figure 3 Protein structure of FXR. (A) General structure of nuclear receptors. A typical nuclear receptor consists of functional domains, such as activation of function 1 domain (AF1), DNA-binding domain (DBD), hinge region (H), ligand-binding domain (LBD), and activation of function 2 domain (AF-2). (B) Schematic representation of ligand-FXR-RXRα complex bound to IR1 element. Arrows indicate the inverted repeats of FXRE. Red pentagon and blue rhombus represent a bile acid molecule and an RXRα agonist, such as 9-cis-retinoic acid, respectively.
Figure 3 Protein structure of FXR. (A) General structure of nuclear receptors. A typical nuclear receptor consists of functional domains, such as activation of function 1 domain (AF1), DNA-binding domain (DBD), hinge region (H), ligand-binding domain (LBD), and activation of function 2 domain (AF-2). (B) Schematic representation of ligand-FXR-RXRα complex bound to IR1 element. Arrows indicate the inverted repeats of FXRE. Red pentagon and blue rhombus represent a bile acid molecule and an RXRα agonist, such as 9-cis-retinoic acid, respectively.CC BY · PubMed Central
Figure 4 Overall physiological function of FGF15/19.
Figure 4 Overall physiological function of FGF15/19.CC BY · PubMed Central
Figure 5 Regulation of BA synthesis by FXR-FGF15/19 signaling axis. Primary BAs (green pentagons) are synthesized from cholesterol (black pentagons) by a series of enzymatic reactions initiated with CYP7A1 in hepatocytes, and are exported from hepatocytes through BSEP, delivered to the duodenum, and converted to secondary BAs (red pentagons) by gut microbiota when traveling through the intestinal tract to help incorporation of fat-soluble nutrients. The rest of BAs are mostly reabsorbed through ASBT on the apical brush border of enterocytes in the ileum and bind to IBABP. The majority of BAs are then transported to the basolateral membrane to be exported into enterohepatic circulation, whereas a fraction of them is transported to the nucleus to form a complex with FXR and liganded RXRα on IR1 located between exon 2 and 3 of Fgf15/FGF19. The complex is then given access to general transcription factor (GTF) complexes on the promoter region (Prom), mediated by the mediator complex (MC), to initiate RNA polymerization by RNA polymerase II (R). Synthesized FGF15/19 (F15/19) is released into enterohepatic circulation and reaches the FGFR4-Klβ complex to activate intracellular events and induce SHP expression in hepatocytes for subsequent suppression of CYP7A1 expression. Exported BAs into enterohepatic circulation are incorporated into hepatocytes through NTCP or OATP and bind to hepatic FXR-RXRα complex on IR1 of SHP to induce expression. The SHP protein then binds to the HNF4α homodier-LRH-1 complex to suppress CYP7A1 expression.
Figure 5 Regulation of BA synthesis by FXR-FGF15/19 signaling axis. Primary BAs (green pentagons) are synthesized from cholesterol (black pentagons) by a series of enzymatic reactions initiated with CYP7A1 in hepatocytes, and are exported from hepatocytes through BSEP, delivered to the duodenum, and converted to secondary BAs (red pentagons) by gut microbiota when traveling through the intestinal tract to help incorporation of fat-soluble nutrients. The rest of BAs are mostly reabsorbed through ASBT on the apical brush border of enterocytes in the ileum and bind to IBABP. The majority of BAs are then transported to the basolateral membrane to be exported into enterohepatic circulation, whereas a fraction of them is transported to the nucleus to form a complex with FXR and liganded RXRα on IR1 located between exon 2 and 3 of Fgf15/FGF19. The complex is then given access to general transcription factor (GTF) complexes on the promoter region (Prom), mediated by the mediator complex (MC), to initiate RNA polymerization by RNA polymerase II (R). Synthesized FGF15/19 (F15/19) is released into enterohepatic circulation and reaches the FGFR4-Klβ complex to activate intracellular events and induce SHP expression in hepatocytes for subsequent suppression of CYP7A1 expression. Exported BAs into enterohepatic circulation are incorporated into hepatocytes through NTCP or OATP and bind to hepatic FXR-RXRα complex on IR1 of SHP to induce expression. The SHP protein then binds to the HNF4α homodier-LRH-1 complex to suppress CYP7A1 expression.CC BY · PubMed Central

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Metadata

Authors
Katafuchi, T., & Makishima, M.
Affiliations
Nihon University (JP)
Corresponding author
Katafuchi, Takeshi
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-05-27
Volume
23
Issue
11
Pages
6046
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23116046
PMC
PMC9181207
OpenAlex
W4281710331
Cited by
193
References
183
Citations by year
2026: 69 · 2025: 52 · 2024: 38 · 2023: 25 · 2022: 9
FWCI
3.81
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science KAKENHI (20K22746)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords
bile acids, farnesoid X receptor, FGF receptor 4, β-Klotho, enterohepatic circulation, nuclear receptor signaling, retinoid X receptor alpha, bile acid metabolism, lipid metabolism, cholesterol metabolism, metabolic syndrome, FXR agonists
MeSH terms
Bile Acids and Salts, Cholesterol, Fibroblast Growth Factors, Liver, Signal Transduction, Receptors, Cytoplasmic and Nuclear

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