Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence

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.

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

“…A few studies have recently revealed that cellular senescence can be regulated by nuclear receptors (Graziano, Johnston, Deng, Zhang, & Gonzalo, 2016; Jin et al, 2016; O'Loghlen et al, 2015; Wu et al, 2015; Zambrano et al, 2014; Zhu et al, 2014). Nuclear receptors form a large family, and only a few of them have been implicated so far in cellular senescence.…”

rSjP40 protein promotes PPARγ expression in LX‐2 cells through microRNA‐27b

“…PPARg is also reported to be involved in liver fibrosis. During the activation process of HSCs and liver fibrosis, PPARg expression is gradually lowered, whereas it is highly expressed in quiescent HSCs (21,22). Overexpression of PPARg in activated HSCs switches HSCs to a more quiescent phenotype and strengthens adipogenic ability of HSCs (23).…”

Hepatic stellate cells as key target in liver fibrosis

“…Curcumin regulates PPARγ coactivator-1α expression by AMPK pathway in HSCs in vitro [217]. Activation of PPARγ/p53 signaling is required for curcumin to induce HSC senescence [218]. Thiazolidinediones (TZDs), synthetic insulin sensitizing PPARγ agonists such as pioglitazone and rosiglitazone, improved steatosis and lobular inflammation but not fibrosis in non-cirrhotic NASH patients in a phase 3 trial (PIVENS trial) [219].…”

“…Soluble egg antigens (SEA) of schistosoma japonicum induce senescence of activated HSCs by activating FoxO3a/SKP2/p27 pathway [317]. HSC senescence can also be induced by phytochemicals such as curcumin by activating PPARγ/p53 signaling [218]. RAR/RXR and PPARγ may play a role in inducing HSC senescence as antifibrotic therapy [318].…”