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Targeting Oxidative Stress for the Treatment of Liver Fibrosis

  • Theerut Luangmonkong
  • Su Suriguga
  • Henricus A. M. Mutsaers
  • Geny M. M. Groothuis
  • Peter Olinga
  • Miriam Boersema
Chapter
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 175)

Abstract

Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.

Keywords

Liver fibrosis Oxidative stress Reactive oxygen species Therapeutic target 

Abbreviations

ADP

Adenosine diphosphate

ALD

Alcoholic liver disease

ALT

Alanine transaminase

BDL

Bile duct-ligated

Ca2+

Calcium

CCl4

Carbon tetrachloride

CoA

Coenzyme A

CoQ10

Coenzyme Q10

CYP

Cytochrome P450

CytC

Cytochrome C

DHA

Docosahexaenoic acid

ECM

Extracellular matrix

eIF2α

Eukaryotic translation initiation factor 2 alpha

EPA

Eicosapentaenoic acid

ER

Endoplasmic reticulum

Ero1α

Endoplasmic reticulum oxidoreductin 1 alpha

FADH2

Flavin adenine dinucleotide

GSH

Glutathione

H2O2

Hydrogen peroxide

HBV

Hepatitis B virus

HCV

Hepatitis C virus

HMGB

High-mobility group box

HNE

4-Hydroxynonenal

HO

Hydroxyl radical

HSC

Hepatic stellate cells

IRAK-1

Interleukin-1 receptor-associated kinase-1

KC

Kupffer cells

Ldlr

Low-density lipoprotein receptor

LPS

Lipopolysaccharide

MDA

Malondialdehyde

NADH

Nicotinamide adenine dinucleotide

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

NFE2L2

Nuclear factor (erythroid-derived 2)-like 2

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3

Nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3

NOX

NADPH oxidase

O2

Oxygen

O2•−

Superoxide anion

PDGF

Platelet-derived growth factor

PDI

Protein disulfide isomerase

PERK

Protein kinase R (PKR)-like endoplasmic reticulum kinase

ROS

Reactive oxygen species

TGF-β

Transforming growth factor beta

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor alpha

UPR

Unfolded protein response

Notes

Conflict of Interest

No conflict of interest.

Financial Support

This work was supported by ZonMw (grant number: 114021010), China Scholarship Council, and Lundbeckfonden (grant number: R231-2016-2344).

Author’s Contributions

T. Luangmonkong and S. Suriguga, searching, analyzing, and selecting publications and drafting and editing of the manuscript; H. A. M. Mutsaers and G. Groothuis, revising of the manuscript for important intellectual content; P. Olinga, supervising the scope of the manuscript and revising the manuscript for important intellectual content; M. Boersema, reviewing the drafted manuscript and contributing important intellectual content to the final manuscript.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Theerut Luangmonkong
    • 1
    • 2
  • Su Suriguga
    • 1
  • Henricus A. M. Mutsaers
    • 1
    • 3
  • Geny M. M. Groothuis
    • 4
  • Peter Olinga
    • 1
  • Miriam Boersema
    • 1
  1. 1.Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenThe Netherlands
  2. 2.Department of Pharmacology, Faculty of PharmacyMahidol UniversityBangkokThailand
  3. 3.Department of Clinical MedicineAarhus UniversityAarhusDenmark
  4. 4.Department of Pharmacokinetics, Toxicology and TargetingUniversity of GroningenGroningenThe Netherlands

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