Abstract
Hepatic stellate cells (HSCs) are involved in the pathogenesis of liver fibrosis. Resveratrol, 3,5,4′-trihydroxystilbene, is a dietary polyphenol found in natural food products. Here, we evaluated the anti-proliferative effects of a synthetic resveratrol derivative, 3,5-diethoxy-3′-hydroxyresveratrol (DEHR), on HSCs. Flow cytometry and Western blot analyses showed that DEHR induces apoptosis through the upregulation of cleaved caspase-3 and poly (ADP-ribose) polymerase expression and reduction in the level of an anti-apoptotic protein B-cell lymphoma 2 (Bcl2). As caveolin-1 (CAV1), a competitive inhibitor of heme oxygenase 1 (HO-1), is related to apoptotic proteins in hepatic cells, we focused on the role of CAV1 in DEHR-induced apoptosis in HSCs through Western blot analyses. Our results showed that the inhibitory effect of DEHR on cell viability was stronger in HO-1 siRNA-transfected cells but weakened in CAV1 siRNA-transfected cells. Collagen concentration was significantly reduced, whereas CAV1 expression increased after treatment of a bile duct ligation injury-induced liver fibrosis model with DEHR for four weeks. We confirmed that DEHR treatment significantly reduced fibrous hyperplasia around the central veins, using hematoxylin and eosin and Sirius red staining. DEHR ameliorates liver fibrosis in vitro and in vivo, possibly through a mechanism involving CAV1.
Highlights
Liver fibrosis is a severe disease caused by chronic liver injury in response to oxidative stress, viral infection, and biliary disorders [1]
We investigated whether diethoxy-30 -hydroxyresveratrol (DEHR) induces apoptosis in hepatic stellate cells (HSCs)-T6 cells via CAV1 and attenuates liver fibrosis in a bile duct ligation (BDL)-induced mouse model
To investigate whether DEHR induces apoptosis in HSCs, we examined the apoptotic effect of DEHR using flow cytometry and Western blot analyses
Summary
Liver fibrosis is a severe disease caused by chronic liver injury in response to oxidative stress, viral infection, and biliary disorders [1]. Results of studies that explored the inhibitory effects of resveratrol on the proliferation of HSCs have implicated resveratrol as a promising candidate for the treatment of liver fibrosis [14,15,16,17]. As HO-1 is associated with cell proliferation, drugs capable of regulating HO-1 expression are considered potential therapeutic candidates for the treatment of liver fibrosis [2,21]. CAV1 expression reportedly regulated the cytotoxic and pro-apoptotic activities of resveratrol in dose- and time-dependent manners in a hepatocellular carcinoma animal model [21]. We investigated the cytotoxic effect of a synthetic resveratrol derivative, 3,5-diethoxy-30 -hydroxyresveratrol (DEHR), in HSCs in vitro. We determined CAV1 expression and collagen concentration in the BDL-induced liver fibrosis model after treatment with DEHR
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