MDP induces the senescence of activated hepatic stellate cells through
regulating Ago2/miR-708/ZEB1/p53 pathway
Abstract
Background and Purpose: Extracellular matrix (ECM) is mainly derived
from activated hepatic stellate cells (HSC), and its excessive
deposition is one of the characteristics of liver fibrosis. Monomer
derivative of paeoniflorin (MDP) inhibits inflammatory responses.
However, the role and fundamental mechanism of MDP in liver fibrosis was
still unclear. Experimental Approach: The effect of MDP was evaluated on
CCl4-induced C57BL/6J mice and TGF-β1-induced LX-2 cells. The level of
SA-β-Gal was detected by SA-β-Gal kits. The cell cycle was evaluated by
flow cytometry. The expression of p16, p21, α-SMA and Col. I proteins
were analyzed by qRT-PCR, Western blots and immunofluorescence staining
and IHC staining. The pathological changes of liver tissue were
evaluated by histological analysis. Key Results: We demonstrated that
MDP inhibited the progression of liver fibrosis in vivo and in vitro,
concomitant with the elevated expression of Ago2, miR-708 and p53 as
well as the downregulated expression of ZEB1. MDP could combined with
Ago2. Upregulation of miR-708 and p53 and downregulation of ZEB1
increased the number of SA-β-Gal-positive HSCs and the expression levels
of p16 and p21 as well as decreased the expression of α-SMA and Col. I
in activated HSCs. Meanwhile, miR-708 directly targeted ZEB1, thus
inhibiting the mRNA of ZEB1. ZEB1 could bind to the E‐box of p53
promoter and restrain its promoter activity as well as thus block the
expression of p53. Conclusion and Implications: MDP could induce
senescence of activated HSCs via regulating Ago2/miR-708/ZEB1/p53 aixs
and may be applied to treat liver fibr