Our previous studies have confirmed that cadmium (Cd) exposure causes hepatotoxicity; it also induces autophagy and blocks the autophagy flux. Therefore, we hypothesized that Cd hepatotoxicity could be alleviated through nutritional intervention. Taurine (Tau) has various biological functions such as acting as an antioxidant, acting as an anti−inflammatory, and stabilizing cell membranes. In order to explore the protective effect and internal mechanism of Tau on Cd−induced hepatotoxicity, normal rat liver cell line BRL3A cells were treated with Cd alone or in combination with Tau to detect cell injury and autophagy−related indexes in this study. We found that Tau can alleviate Cd−induced cell−proliferation decline and morphological changes in the cell. In addition, Tau activates autophagy and alleviates the blockage of Cd−induced autophagy flux. In this process, lysosome acidification and degradation were enhanced, and autophagosomes were further fused with lysosomes. Then, we found that Tau alleviated autophagic flux block by promoting the transfer of membrane fusion proteins STX17 and SNAP29 to autophagosomes and the translocation of VAMP8 to lysosomes, which in turn attenuated the hepatocyte injury induced by Cd exposure. This will further reveal the hepatotoxicity mechanism of Cd and provide the theoretical basis for the prevention and treatment of Cd poisoning.
As a common environmental pollutant, cadmium (Cd) causes damage to many organs of the body. Gap junction intercellular communication (GJIC) represents one of the most important routes of rapid signaling between cells. However, the mechanisms underlying GJIC's role in hepatotoxicity induced by Cd remain unknown. We established a Cd poisoning model in vitro by co‐culturing Cd‐exposed and unexposed hepatocytes and found that 18β‐glycyrrhetinic acid (GA), a GJIC inhibitor, can effectively reduce the apoptosis rate of healthy cells co‐cultured with apoptotic cells treated with Cd. We also found that anti‐FasL antibody had the same effect. However, in mono‐cultured cells, GA treatment in combination with Cd was found to aggravate the damage induced by Cd exposure, increase the level of oxidative stress and protein expression of HO‐1, decrease the mitochondrial membrane potential, incur more serious morphological damage to mitochondria than Cd treatment alone. Moreover, compared with Cd‐only exposure, GA and Cd co‐treatment further increased the expression levels of the apoptosis‐related proteins Fas, FasL, FADD and the ratio of Bax/Bcl‐2, inhibited the protein expression of ASK1 and Daxx. We also found that the protein expression of Daxx in siFADD + Cd hepatocytes was significantly higher than in Cd‐treated cells. Thus, our study suggests that gap junction inhibition may play a dual role in Cd‐induced cell damage by inhibiting the transmission of death signals from damaged cells to healthy cells but also aggravating the transmission of death signals between damaged cells, and that the Fas/FasL‐mediated death receptor pathway may play an important role in this process.
Gap junction protein connexin 43 (Cx43) plays a critical role in gap junction communication in rat hepatocytes. However, those located between hepatocytes are easily internalized following exposure to poisons. Herein, we investigated the potential of buffalo rat liver 3A (BRL 3A) cells to generate annular gap junctions (AGJs) proficient at alleviating cadmium (Cd) cytotoxic injury through degradation via an endosome–lysosome pathway. Our results showed that Cd-induced damage of liver microtubules promoted Cx43 internalization and increased Cx43 phosphorylation at Ser373 site. Furthermore, we established that Cd induced AGJs generation in BRL 3A cells, and AGJs were subsequently degraded through the endosome–lysosome pathway. Overall, our results suggested that Cx43 internalization and the generation of AGJs were cellular protective mechanisms to alleviate Cd toxicity in rat hepatocytes.
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