Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling
Abstract
:1. Introduction
2. The Enterohepatic Circulation and Kinetics of BA and the FXR–FGF19 Dynamics
3. Regulation of BA Homeostasis: The Role of Gut Microbiota
4. The Microbiota–BA–FXR Axis
5. Fibroblast Growth Factors FGF15 and Human Ortholog FGF19
6. FXR–FGF19 and BA Homeostasis
7. FXR–FGF15/19 Pathway and Metabolic Effects
7.1. Lipid Homeostasis
7.2. Glucose Homeostasis and Gluconeogenesis
7.3. FGF19 and Role in Glycogen Synthesis
7.4. FGF19 and Role in Protein Synthesis
7.5. FGF19 and Role in Energy Expenditure
8. The Role of FXR in Liver Disease
8.1. Inflammation and Fibrosis
8.2. Cholestasis
9. FXR as a Therapeutic Target?
9.1. FGF19 and FGF21 Variants
9.2. FXR Agonists
Obeticholic acid (approved for the treatment of primary biliary cholangitis) | [238,239,240,241] |
Tropifexor (LJN452) | [242,243,244,245,246,247,248,249] |
Cilofexor (GS-9674) | [250,251] |
Vonafexor | [252] |
Nidufexor | [253] |
GW4064 | [254] |
MET409 | [255] |
TC-100 | [256] |
BMS-986339 | [257] |
HEC96719 | [258] |
WAY-450 | [259] |
WAY-362450 | [260] |
Px-102 | [261] |
Px-104 | [262] |
TERN-101 | [263] |
EDP-305 | [264] |
INT-767 (FXR-TGR5 dual agonist) | [25,265,266] |
10. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
3β-HSD | 3β-hydroxy-D5-C27-steroid dehydroxylase |
6-ECDCA | 6a-ethyl-chenodeoxycholic acid |
ACC2 | Acetyl CoA carboxylase |
AGRP | Agouti-related peptide |
AKR1C4 | 3a-hydroxysteroid dehydrogenase |
AKR1D1 | D4-3-oxosteroid 5b-reductase |
AKT | Protein kinase B |
ALT | Alanine aminotransferase |
AMPs | Antimicrobial peptides |
ASBT | Apical sodium-dependent bile salt transporter |
BA | Bile acids |
BAAT | Bile acid-CoA:amino acid N-acyltransferase |
BACS | Bile acid CoA synthase |
ABCB11 | Bile acid export pump |
BAT | Brown adipose tissue |
BSEP | Bile salt export pump |
BSH | Bile salt hydrolase |
C4 | 7a-hydroxy-4-cholesten-3-one |
CA | Cholic acid |
CCK | Cholecystokinin |
CCl4 | Carbon tetrachloride |
CDCA | Chenodeoxycholic acid |
CF | Cycling frequency |
COX-2 | Cylcooxygenase-2 |
CREB | cAMP regulatory element binding protein |
CYP7A1 | Cholesterol-7α-hydroxylase |
CYP27A1 | Cytochrome P450 27A1 |
CYP2A12 | Cytochrome P450 2A12 |
CYP2C70 | Cytochrome P450 2C70 |
CYP7A1 | Cytochrome P450 7A1 |
CYP7B1 | Cytochrome P450 7B1 |
CYP8B1 | Cytochrome P450 8B1 |
DBD | DNA binding domain |
DCA | Deoxycholic acid |
eIF4B | Eukaryotic initiation factor 4B |
eIF4E | Eukaryotic initiation factor 4E |
ER2 | Everted hexanucleotide repeat separated by 2 nucleotides |
ERK | Extracellular-signal-regulated protein kinase |
FAR | Fractional absorption rate |
FFA | Free fatty acid |
FGF | Fibroblast growth factor |
FGF15 | Fibroblast growth factor 15 |
FGF19 | Fibroblast growth factor 19 |
FGFR | Fibroblast growth factor receptor |
FGFR1 | Fibroblast growth factor receptor 1 |
FGFR4 | Fibroblast growth factor receptor 4 |
FLINT | Farnesoid X receptor ligand obeticholic acid in NASH treatment |
FXR | Farnesoid X receptor |
FXRE | Farnesoid X receptor response element |
FTR | Fractional turnover rate |
GGT | Gamma-glutamyltransferase |
GLP-1 | Glucagon-like peptide 1 |
GLUT2 | Glucose transporter 2 |
GPBAR-1 | G-protein-coupled bile acid receptor-1 |
GS | Glycogen synthase |
GSK3a | Glycogen synthase kinase 3a |
HREs | Hormone response elements |
HSC | Hepatic stellate cell |
IkB | Inhibitor of nuclear factor kappa B |
IBABP | Intestinal bile acid binding protein |
IFN-g | Interferon-gamma |
iNOS | Inducible nitric oxide synthase |
IR1 | Inverted hexanucleotide repeat separated by 1 nucleotide |
KO | Knockout |
LBD | Ligand-binding domain |
LCA | Lithocholic acid |
LRH-1 | Liver receptor homologue 1 |
LPS | Lipopolysaccharide |
JNK | JUN N-terminal kinase |
JUN | Jun proto-oncogene |
MAGs | Metagenome-assembled genomes |
MCA | Muricholic acid |
MCD | Methionine-choline deficient |
MCP-1 | Monocyte chemoattractant protein-1 |
MRP2 | Multidrug resistance-associated protein 2 |
mTOR | Mammalian target of rapamycin |
NAFLD | Non-alcoholic fatty liver disease |
NASH | Non-alcoholic steatohepatitis |
NF-kB | Nuclear factor kappa-light chain enhancer of activated B cell |
NPY | Neuropeptide Y |
NR s | Nuclear receptors |
NLRP3 | NACHT LRR and PYD domains-containing protein 3 |
NTCP | Sodium taurocholate co-transporting polypeptide |
OATP | Organic anion transporting polypeptide |
OCA | Obeticholic acid |
OSTα | Organic solute transporter alpha |
OSTb | Organic solute transporter beta |
P90RSK | p90 ribosomal S6 kinase |
PBC | Primary biliary cirrhosis |
PEPCK | Phosphoenolpyruvate carboxykinase |
PFIC | Progressive familial intrahepatic cholestasis |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PGC-1b | Peroxisome proliferator-activated receptor gamma coactivator 1-beta |
PPARγ | Peroxisomal proliferator activated receptor gamma |
PXR | Pregnane X receptor |
RCT | Reverse cholesterol transport |
RXR | Retinoid X receptor |
S1PR2 | Sphingosine-1-phosphate receptor 2 |
S6K1 | S6 kinase beta-1 |
SCD1 | Stearoyl-CoA desaturase 1 |
SIBO | Small intestinal bacterial overgrowth |
SHP | Small heterodimer partner |
SREBP1c | Sterol regulatory element-binding protein 1c |
STAT3 | Signal transducer and activator of transcription 3 |
SULT2A1 | Sulfotransferase 2A1 |
TCA | Taurocholic acid |
TDCA | Taurodeoxycholic acid |
TGR5 | Takeda G-protein receptor 5 |
TLCA | Taurolithocholic acid |
TNFα | Tumor necrosis factor alpha |
VDR | Vitamin D receptor |
VLDL | Very low-density lipoprotein |
WAT | White adipose tissue |
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Di Ciaula, A.; Bonfrate, L.; Baj, J.; Khalil, M.; Garruti, G.; Stellaard, F.; Wang, H.H.; Wang, D.Q.-H.; Portincasa, P. Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling. Nutrients 2022, 14, 4950. https://doi.org/10.3390/nu14234950
Di Ciaula A, Bonfrate L, Baj J, Khalil M, Garruti G, Stellaard F, Wang HH, Wang DQ-H, Portincasa P. Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling. Nutrients. 2022; 14(23):4950. https://doi.org/10.3390/nu14234950
Chicago/Turabian StyleDi Ciaula, Agostino, Leonilde Bonfrate, Jacek Baj, Mohamad Khalil, Gabriella Garruti, Frans Stellaard, Helen H. Wang, David Q.-H. Wang, and Piero Portincasa. 2022. "Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling" Nutrients 14, no. 23: 4950. https://doi.org/10.3390/nu14234950