Ursodeoxycholic acid alleviates experimental liver fibrosis involving inhibition of autophagy.
Life Sci
; 242: 117175, 2020 Feb 01.
Article
in En
| MEDLINE
| ID: mdl-31843528
ABSTRACT
AIMS:
Ursodeoxycholic acid (UDCA) has been widely used in the treatment of primary biliary cholangitis (PBC) with chronic liver fibrosis, but its detailed mechanism remains unclear. This study was aimed to determine whether autophagic signaling is involved in the therapeutic effect of UDCA on liver fibrosis.METHODS:
By using hepatic stellate cell (HSC) line LX2 and CCl4-induced fibrotic rat model, autophagy signaling was investigated by western blotting and mRFP-EGFP-LC3 tandem fluorescent tagged plasmid (ptfLC3) transfection technique. Anti-fibrotic profile was determined by western blotting, qRT-PCR, MTT assay, trypan blue, hydroxyproline assay and Masson staining. KEYFINDINGS:
TGFß1 treatment decreased P62 accumulation and increased both autophagosomes and autolysosomes in LX2 cells, thereby elevated autophagic flux. Hydroxychloroquine (HCQ), antagonist of autophagy, was found to dramatically inhibit COL1A2 mRNA expression and cell proliferation in a dose-dependent manner. This coincides with the effect of UDCA intervention on collagen aggradation and cell viability. Meanwhile, UDCA inhibited TGFß1-induced autophagy flux. And rapamycin, agonist of autophagy, was found to impair the anti-fibrotic effect of UDCA. Moreover, study in vivo showed that UDCA alone or in combination with HCQ restored the CCl4-induced liver fibrosis in rodent models with autophagy inhibited profile.SIGNIFICANCE:
Taken together, our study revealed that UDCA displays anti-fibrotic role by protecting HSC against production of collagen and inhibiting cellular viability involving autophagy inhibition and provide a new insight into the pharmacological basis of UDCA treatment for hepatic fibrosis.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autophagy
/
Ursodeoxycholic Acid
/
Liver Cirrhosis
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Life Sci
Year:
2020
Document type:
Article
Publication country:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS