Abstract
Nonalcoholic steatohepatitis (NASH) is within the spectrum of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). The prevalence of NASH is rising and has become a large burden to the medical system worldwide. Unfortunately, despite its high prevalence and severe health consequences, there is currently no therapeutic agent approved to treat NASH. Therefore, the development of efficacious therapies is of utmost urgency and importance. Many molecular targets are currently under investigation for their ability to halt NASH progression. One of the most promising and well-studied targets is the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR). In this chapter, the characteristics, etiology, and prevalence of NASH will be discussed. A brief introduction to FXR regulation of BA homeostasis will be described. However, for more details regarding FXR in BA homeostasis, please refer to previous chapters. In this chapter, the mechanisms by which tissue and cell type-specific FXR regulates NASH development will be discussed in detail. Several FXR agonists have reached later phase clinical trials for treatment of NASH. The progress of these compounds and summary of released data will be provided. Lastly, this chapter will address safety liabilities specific to the development of FXR agonists.
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Abbreviations
- αSMA:
-
Alpha smooth muscle actin
- βKL:
-
Beta KLOTHO
- AGRP:
-
Agouti-related peptide
- ALP:
-
Alkaline phosphatase
- ALT:
-
Alanine aminotransferase
- AP-1:
-
Activator protein 1
- ApoA-IV:
-
Apolipoprotein A-IV
- ApoC-III:
-
Apolipoprotein C-III
- ApoE:
-
Apolipoprotein E
- ASBT:
-
Apical sodium-dependent bile acid transporter
- BA:
-
Bile acid
- BBB:
-
Blood-brain barrier
- bFKB1:
-
Bi-specific activating antibody of FGFR1 and β-Klotho
- BSH:
-
Bile salt hydrolase
- C4:
-
7α-hydroxy-4-cholesten-3-one
- CA:
-
Cholic acid
- CAPE:
-
Caffeic acid phenethyl ester
- CCl4 :
-
Carbon tetrachloride
- CDCA:
-
Chenodeoxycholic acid
- COL1α1:
-
Collagen type 1, α1
- CREB:
-
cAMP response element-binding protein
- CRP:
-
C-reactive protein
- CTGF:
-
Connective tissue growth factor
- CYP27A1:
-
Cytochrome P450 27A1
- CYP7A1:
-
Cytochrome P450 7A1
- CYP8B1:
-
Cytochrome P450 8B1
- DCA:
-
Deoxycholic acid
- DDAH2:
-
Dimethylarginine dimethylaminohydrolase 2
- EETs:
-
Epoxyeicosatrienoic acids
- eNOS:
-
Endothelial nitric oxide synthase
- ERK:
-
Extracellular signal-regulated kinases
- ET-1:
-
Endothelin-1
- FGF15:
-
Fibroblast growth factor 15
- FGF19:
-
Fibroblast growth factor 19
- FGF21:
-
Fibroblast growth factor 21
- FGFR1:
-
Fibroblast growth factor receptor 1
- FGFR4:
-
Fibroblast growth factor receptor 4
- FXR:
-
Farnesoid X receptor
- FXRRE:
-
Farnesoid X receptor response element
- G6Pase:
-
Glucose 6-phosphatase
- GGT:
-
γ-Glutamyltransferase
- GLP1:
-
Glucagon-like peptide-1
- Gly-MCA:
-
Glycine-conjugated muricholic acid
- HCC:
-
Hepatocellular carcinoma
- HCV:
-
Hepatitis C virus
- HDL:
-
High-density lipoprotein
- HFD:
-
High-fat diet
- HOMA-IR:
-
Homeostatic model assessment of β-cell function and insulin resistance
- IκBα:
-
Nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha
- ICV:
-
Intracerebral-ventricular injection
- IKKβ:
-
Inhibitor of nuclear factor kappa-B kinase subunit beta
- JNK:
-
c-Jun N-terminal kinase
- LCA:
-
Lithocholic acid
- LDL:
-
Low-density lipoprotein
- LDLR:
-
Low-density lipoprotein receptor
- LPS:
-
Lipopolysaccharide
- MCA:
-
Muricholic acid
- MCD:
-
Methacholine-deficient diet
- MCP-1:
-
Macrophage chemoattractant protein 1
- MMP2:
-
Matrix metalloprotease 2
- NAFLD:
-
Nonalcoholic fatty liver disease
- NAS:
-
NAFLD activity score
- NASH:
-
Nonalcoholic steatohepatitis
- NFκB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- NKT:
-
Natural killer T cell
- NPY:
-
Neuropeptide Y
- OCA:
-
Obeticholic acid
- PBC:
-
Primary biliary cirrhosis
- PDC:
-
Pyruvate dehydrogenase complex
- PDK4:
-
Pyruvate dehydrogenase kinase 4
- PEPCK:
-
Phosphoenolpyruvate carboxykinase
- PGC1α:
-
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- PIIINP:
-
N-terminal propeptide of type III collagen
- PNPLA3:
-
Patatin-like phospholipase domain-containing protein 3
- PPARα:
-
Peroxisome proliferator-activated receptor alpha
- PPARγ:
-
Peroxisome proliferator-activated receptor gamma
- Pro-C3:
-
N-terminal type III collagen propeptide
- RXR:
-
Retinoid X receptor
- SAA3:
-
Serum amyloid A3
- SAF:
-
Steatosis, activity, and fibrosis scoring system
- SAP:
-
Serum amyloid P
- SHP:
-
Small heterodimer partner
- SRB1:
-
Scavenger receptor class B type 1
- SREBP1c:
-
Sterol regulatory element-binding protein 1c
- TβMCA:
-
Taurine-conjugated beta-muricholic acid
- TCA:
-
Taurocholic acid
- TGFβ:
-
Transforming growth factor beta
- TGFβR2:
-
Transforming growth factor beta receptor 2
- TGR5:
-
Takeda G-protein receptor 5
- TIMP1:
-
Tissue inhibitor of metalloproteases 1
- TNFα:
-
Tumor necrosis factor alpha
- UCP1:
-
Uncoupling protein 1
- UDCA:
-
Ursodeoxycholic acid
- VLDL:
-
Very low-density lipoprotein
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Schumacher, J.D., Guo, G.L. (2019). Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_228
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