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Bile Acids and Their Receptors pp 325–357Cite as

Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 256))

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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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA

    Justin D. Schumacher & Grace L. Guo

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  1. Justin D. Schumacher
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  2. Grace L. Guo
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Correspondence to Grace L. Guo .

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  1. University of Perugia, School of Medicine, Perugia, Italy

    Stefano Fiorucci

  2. S.C. Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy

    Eleonora Distrutti

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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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