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2017 ; 8
(6
): e2886
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Interaction between autophagy and senescence is required for dihydroartemisinin
to alleviate liver fibrosis
#MMPMID28617435
Zhang Z
; Yao Z
; Zhao S
; Shao J
; Chen A
; Zhang F
; Zheng S
Cell Death Dis
2017[Jun]; 8
(6
): e2886
PMID28617435
show ga
Autophagy and cellular senescence are stress responses essential for homeostasis.
Therefore, they may represent new pharmacologic targets for drug development to
treat diseases. In this study, we sought to evaluate the effect of
dihydroartemisinin (DHA) on senescence of activated hepatic stellate cells
(HSCs), and to further elucidate the underlying mechanisms. We found that DHA
treatment induced the accumulation of senescent activated HSCs in rat fibrotic
liver, and promoted the expression of senescence markers p53, p16, p21 and Hmga1
in cell model. Importantly, our study identified the transcription factor GATA6
as an upstream molecule in the facilitation of DHA-induced HSC senescence. GATA6
accumulation promoted DHA-induced p53 and p16 upregulation, and contributed to
HSC senescence. By contrast, siRNA-mediated knockdown of GATA6 dramatically
abolished DHA-induced upregulation of p53 and p16, and in turn inhibited HSC
senescence. Interestingly, DHA also appeared to increase autophagosome generation
and autophagic flux in activated HSCs, which was underlying mechanism for
DHA-induced GATA6 accumulation. Autophagy depletion impaired GATA6 accumulation,
while autophagy induction showed a synergistic effect with DHA. Attractively, p62
was found to act as a negative regulator of GATA6 accumulation. Treatment of
cultured HSCs with various autophagy inhibitors, led to an inhibition of
DHA-induced p62 degradation, and in turn, prevented DHA-induced GATA6
accumulation and HSC senescence. Overall, these results provide novel
implications to reveal the molecular mechanism of DHA-induced senescence, by
which points to the possibility of using DHA based proautophagic drugs for the
treatment of liver fibrosis.
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