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

  • Justin D. Schumacher
  • Grace L. GuoEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series

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.

Keywords

Bile Acids FGF15 FGF19 FXR NASH 

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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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyRutgers UniversityPiscatawayUSA

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