Resveratrol Inhibits Hepatic Stellate Cell Activation via the Hippo Pathway

Abstract

Liver fibrosis, which results from chronic liver injury due to factors such as chronic alcohol consumption, hepatitis virus infections, and immune attacks, is marked by excessive deposition of extracellular matrix (ECM). Resveratrol (Res), a polyphenol phytoalexin, has been demonstrated to show anti-inflammatory, antioxidative, antiproliferative, and chemopreventive activities. In recent years, Res has been found to inhibit liver fibrosis. Enhanced Hippo pathway activation has also been reported to inhibit tumor progression and liver fibrosis. In the present study, the role of the Hippo pathway in mediating the effects of Res on hepatic stellate cells (HSCs) was examined. We found that Res significantly suppresses HSC proliferation, reducing the cell index. Res induced HSC inactivation, reducing collagen deposition and α-smooth muscle actin (α-SMA) expression. In addition, Res contributed to HSC apoptosis, upregulating Bax and downregulating Bcl-2 expression. Notably, the Hippo pathway was involved in the Res-mediated suppression of HSC activation. Res enhanced the activation of the Hippo pathway and reduced yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) expression. Interestingly, the YAP overexpression inhibited Res-induced HSC inactivation and apoptosis. In conclusion, these results demonstrate that Res inhibits HSC activation, at least in part, via the Hippo pathway. The present study indicates a new antifibrotic mechanism of Res and provides novel insights into Hippo-mediated HSC apoptosis and HSC activation in liver fibrosis.

Polydatin attenuates tubulointerstitial fibrosis in diabetic kidney disease by inhibiting YAP expression and nuclear translocation

“…Resveratrol, an aglycone of PD, has recently been proved to inhibit the activation of hepatic stellate cells by activating Hippo pathway-mediated YAP inhibition, thus playing an anti-fibrosis role (Li et al, 2021). Although YAP signaling is closely associated with the progression of renal fibrosis, little is known the effect of PD on YAP regulation.…”

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

“…First, Res restrains the activation of HSCs mediated through Hippo pathway. This is a novel anti-fibrotic mechanism of Res that could contribute new insights into Hippo-mediated apoptosis of HSCs [222] . Second, RSV also invoked autophagy as well as triggered miR-20a-mediated PTEN/PI3K/AKT signal pathway to weaken LF [220] .…”

New Insights into Hippo/YAP Signaling in Fibrotic Diseases

“…In the liver, HSCs are the principal source of pathologic myofibroblasts; HSC activation during chronic liver injury leads to enormous deposition of ECM which drives fibrosis, loss of function, and ultimately cirrhosis [74]. YAP/TAZ signaling is a crucial regulator of HSC activation in liver fibrosis [11][12][13][14]. YAP was found to be localized in the nucleus in HSCs derived from fibrotic livers in patient and mice models, while YAP nuclear localization was not observed in healthy livers [94].…”

“…Numerous cell types, including epithelial and endothelial cells are also able to transdifferentiate into myofibroblastic phenotype (such as epithelial-mesenchymal transition and endothelial-mesenchymal transition) during organ fibrogenesis [4]. Recent studies have implicated the contribution of Hippo signaling pathway components in the fibrosis of various tissues, including the lung [5][6][7], liver [8][9][10][11][12][13][14], kidney [15][16][17], and heart [18][19][20]. The Hippo signaling pathway was first identified and illustrated in Drosophila.…”

“…For example, the nuclear YAP/TAZ in resident cardiac fibroblasts obtained from preclinical myocardial infarction (MI) models [18,19,27], are sufficient to direct the transdifferentiation of cardiac fibroblasts into pathological myofibroblasts [27,28]. Similarly, YAP/TAZ are important regulators of pathological fibroblast activation in pulmonary fibrosis [5] and hepatic stellate cell activation in liver fibrosis [11][12][13][14]. Furthermore, activated YAP/TAZ in interstitial myofibroblasts promotes kidney fibrosis [16], while hyperactivated YAP/TAZ in nonfibroblast cells, such as macrophages [29,30], epithelial cells [31][32][33], and hepatocytes [8,10] contribute to the pathogenesis of fibrosis.…”