Hepatic stellate cells as key target in liver fibrosis

Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellula...

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Bibliographic Details
Published inAdvanced drug delivery reviews Vol. 121; pp. 27 - 42
Main Authors Higashi, Takaaki, Friedman, Scott L., Hoshida, Yujin
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 01.11.2017
Subjects
Alcoholic liver disease
Cirrhosis
Hepatitis
Myofibroblast
Non-alcoholic fatty liver disease
Non-alcoholic steatohepatitis
CXCL
RAR
TWEAK
ATX
JNK
NF-kB
HMGB1
TNF
DNMT
PRR
Hepatitis
UTR
PPAR
Th
UPR
HSC
iNOS
LRAT
Non-alcoholic steatohepatitis
HBV
Hh
IL
SREBP
FGF
HGF
AT1R
DKK1
ER
ARB
MMP
Cirrhosis
TGF
VAP-1
CCl4
ROS
AMPK
LY6C
HCV
LPA
CVCR
ERK
FXR
MeCP2
NO
NAFLD
LSEC
Myofibroblast
BDL
RXR
CpG
TLR
CB
ACE
EGF
VDR
ASK1
VEGF
NASH
OCA
CCL
ECM
Alcoholic liver disease
PAMP
STAT
5-HT(2B)
CCR
PDGF
Non-alcoholic fatty liver disease
DAMP
EZH2
TZD
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Summary:Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies. [Display omitted]
ISSN:0169-409X
1872-8294
DOI:10.1016/j.addr.2017.05.007