Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis.
10.1016/j.apsb.2018.11.004
- Author:
Jiyu ZHOU
1
;
Ningning HUANG
1
;
Yitong GUO
1
;
Shuang CUI
1
;
Chaoliang GE
1
;
Qingxian HE
1
;
Xiaojie PAN
1
;
Guangji WANG
1
;
Hong WANG
1
;
Haiping HAO
1
Author Information
1. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
ALT, alanine aminotransferase;
ANOVA, analysis of variance;
AST, aspartate aminotransferase;
BA, bile acid;
BSEP, bile salt export pump;
Bile acid;
BrdU, bromodeoxyuridine;
CA, cholic acid;
CCl4, carbon tetrachloride;
CDCA, chenodeoxycholic acid;
CHX, cycloheximide;
CYP7A1, cholesterol 7α-hydroxylase;
Col, collagen;
FXR, farnesoid X receptor;
Farnesoid X receptor;
GalN, d-galactosamine;
H&E, hematoxylin and eosin;
HPLC, high performance liquid chromatography;
HSCs, hepatic stellate cells;
Hepatic stellate cell;
Hepatocellular apoptosis;
IDN-6556;
KCs, Kupffer cells;
LPS, lipopolysaccharide;
Liver fibrosis;
OCA, obeticholic acid;
Obeticholic acid;
PBC, primary biliary cholangitis;
RT-PCR, reverse transcription polymerase chain reaction;
SHP, small heterodimer partner;
TGF, transforming growth factor;
TIMP, tissue inhibitor of metalloproteinase;
TNFα, tumor necrosis factor α;
TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling;
α-SMA, α-smooth muscle action
- From:
Acta Pharmaceutica Sinica B
2019;9(3):526-536
- CountryChina
- Language:English
-
Abstract:
Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF (CHX/TNF)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
