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Bile Acid-Induced Liver Injury in Cholestasis

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Cellular Injury in Liver Diseases

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

Bile acids are physiological detergent molecules synthesized from cholesterol exclusively in the hepatocytes. Bile acids play important roles in generating bile flow and facilitating intestinal nutrient absorption. Bile acids are endogenous ligands of nuclear receptors and cell surface G protein-coupled receptors, which regulate various biological processes including metabolism, immune response, and cell proliferation. Cholestasis is a pathological condition where bile flow out of the liver is reduced or blocked, leading to accumulation of bile acids, cell death, and inflammation in the liver. Chronic cholestasis leads to liver fibrosis, cirrhosis, failure, and carcinogenesis. During cholestasis, bile acid-activated signaling regulates bile acid detoxification mechanisms as well as cell survival and proliferation. The hydrophilic bile acid UDCA has been used as the primary cholestasis therapy for decades. Pharmacological agents targeting the bile acid receptors are being developed as novel therapeutics for cholestasis. This chapter summarizes bile acid biology, mechanism of cholestatic liver injury, and current and future bile acid-based therapeutics for cholestasis.

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Abbreviations

UDCA:

Ursodeoxycholic acid

CYP:

Cytochrome p450

CA:

Cholic acid

CDCA:

Chenodeoxycholic acid

DCA:

Deoxycholic acid

MCA:

Muricholic acid

CYP7A1:

Cholesterol 7α-hydroxylase

CYP8B1:

Sterol 12α-hydroxylase

CYP27A1:

Sterol 27-hydroxylase

CYP7B1:

Oxysterol 7α-hydroxylase

BSH:

Bile salt hydrolases

LCA:

Lithocholic acid

BACS:

Bile acyl-CoA synthetase

BACL:

Bile acid-CoA ligase

BAAT:

Bile acid-CoA:amino acid N-acyltransferase

NTCP:

Na+-dependent taurocholate transporter

OATP:

Organic anion transporter

BSEP:

Bile salt export pump

ABC:

ATP-binding cassette transporter

MDR:

Multi-drug resistant

MRP:

MDR-related protein

OST:

Organic solute transporter

ASBT:

Apical sodium-dependent bile salt transporter

I-BABP:

Intestinal bile acid-binding protein

ICP:

Intrahepatic cholestasis of pregnancy

PFIC:

Progressive familial intrahepatic cholestasis

TJP2:

The junction protein 2 gene

PBC:

Primary biliary cirrhosis

PSC:

Primary sclerosing cholangitis

GCDCA:

Glycochenodeoxycholic acid

JNK:

c-Jun N-terminal kinase

PKC:

Protein kinase C

EGFR:

Epidermal growth factor receptor

ROS:

Reactive oxygen species

MPT:

Mitochondrial permeability transition pore

DAMP:

Damage-associated molecular pattern molecules

ERK:

Extracellular signal–regulated kinases

Egr-1:

Early growth response factor 1

TNFα:

Tumor necrosis factor α

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

ICAM:

Intracellular adhesion molecule

FXR:

Farnesoid X receptor

PXR:

Pregnane X receptor

CAR:

Constitutive androgen receptor

RXR:

Retinoid X receptor

GPCR:

G protein-coupled receptor

S1PR:

Sphingosine-1-phosphate receptor

SHP:

Small heterodimer partner

LRH-1:

Liver receptor homolog-1

HNF4α:

Hepatocyte nuclear factor 4α

FGF15:

Fibroblast growth factor 15

FGFR4:

Fibroblast growth factor receptor 4

SULT2A1:

Sulfotransferase 2A1

UGT:

UDP-glucuronosyltransferase

PKA:

Protein kinase A

GLP-1:

Glucagon-like peptide 1

NASH:

Non-alcoholic steatohepatitis

SphK:

Sphingosine kinase

norUDCA:

nor-Ursodeoxycholic

PPARα:

Peroxisome proliferator-activated receptor α

OCA:

Obeticholic acid

GGT:

γ-Glutamyltransferase

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Acknowledgment

This work is supported in part by NIH grant 1R01DK102487-01 (T.L.), the National Center for Research Resources (5P20RR021940-07), and the National Institute of General Medical Sciences (8 P20 GM103549-07) of the National Institutes of Health (T.L.); NIH grants DK58379 (J.C.) and DK44442 (J.C.).

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Tiangang Li

  2. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA

    John Y. L. Chiang

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  1. Tiangang Li
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  2. John Y. L. Chiang
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Correspondence to Tiangang Li .

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Editors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA

    Wen-Xing Ding

  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Xiao-Ming Yin

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Li, T., Chiang, J.Y.L. (2017). Bile Acid-Induced Liver Injury in Cholestasis. In: Ding, WX., Yin, XM. (eds) Cellular Injury in Liver Diseases. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-53774-0_7

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