Abstract
Activation of quiescent hepatic stellate cells (HSCs) is the major event in hepatic fibrogenesis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Although inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSCs, a better understanding of the senescence of activated HSCs can provide a new therapeutic strategy for prevention and treatment of liver fibrosis. The antioxidant curcumin, a phytochemical from turmeric, has been shown to suppress HSC activation in vitro and in vivo. The current work was aimed to evaluate the effect of curcumin on senescence of activated HSCs and to elucidate the underlying mechanisms. In this study, curcumin promoted the expression of senescence marker Hmga1 in rat fibrotic liver. In addition, curcumin increased the number of senescence-associated β-galactosidase-positive HSCs in vitro. At the same time, curcumin induced HSC senescence by elevating the expression of senescence markers P16, P21 and Hmga1, concomitant with reduced abundance of HSC activation markers α-smooth muscle actin and α1(I)-procollagen in cultured HSCs. Moreover, curcumin affected the cell cycle and telomerase activity. We further demonstrated that P53 pharmacological inhibitor pifithrin-α (PFT-α) or transfection with P53 siRNA abrogated the curcumin-induced HSC senescence in vitro. Meanwhile, curcumin disruption of P53 leading to increased senescence of activated HSCs was further verified in vivo. Further studies indicated that curcumin promoted the expression of P53 through a PPARγ activation-dependent mechanism. Moreover, promoting PPARγ transactivating activity by a PPARγ agonist 15d-PGJ2 markedly enhanced curcumin induction of senescence of activated HSCs. However, the PPARγ antagonist PD68235 eliminated curcumin induction of HSC senescence. Taken together, our results provided a novel insight into the mechanisms underlying curcumin inhibition of HSC activation through inducing senescence.
Highlights
Cellular senescence is described as an antiproliferative program that leads to permanent growth arrest in the cell.[7]
Our previous data have sufficiently demonstrated that curcumin protected the liver from histological injury, pathological angiogenesis and fibrogenesis induced by chronic CCl4 injection in rats.[19,20,21]
Results from immunofluorescence staining showed that curcumin increased the expression of senescence marker Hmga[122] in Hepatic stellate cells (HSCs) concomitant with the expression of α-smooth muscle actin (α-SMA), the marker of HSC activation (Figure 1)
Summary
Cellular senescence is described as an antiproliferative program that leads to permanent growth arrest in the cell.[7]. Previous reports demonstrated that curcumin inhibited activation of HSC in vitro by suppressing cell growth and inhibiting production of extracellular matrix (ECM) components.[17] Curcumin promoted the expression of PPARγ and stimulated the activation of PPARγ, which was a precondition for curcumin to inhibit HSC activation.[18] The purpose of the present study was to investigate the signal transduction pathways involved in curcumin induction of activated HSC senescence. We hypothesized that modulation of PPARγ could contribute to curcumin induction of HSC senescence through promoting the expression of P53. We performed in vivo and in vitro experiments to test the hypothesis
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