College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China.
College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; College of Public Health, Nantong University, Nantong, Jiangsu 226000, PR China.
Ecotoxicol Environ Saf. 2021 Dec 20;227:112895. doi: 10.1016/j.ecoenv.2021.112895. Epub 2021 Oct 18.
Cadmium is an environmental pollutant that threatens the health of both humans and animals. Current studies have shown that while hepatotoxic damage induced by cadmium is closely related to autophagy, its intrinsic mechanism has not been elucidated. MicroRNA plays a regulatory role on different stages of autophagy. In this study, we investigated the mechanisms by which microRNA-155 (miR-155) regulate cadmium-induced hepatotoxicity in rat hepatocytes (BRL 3A cells) and in vivo. We found that cadmium exposure could cause liver injury in rats, resulting in a decreased liver index, increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activity, hepatocyte steatosis, and ultrastructure damage. Cadmium exposure also induced autophagy in hepatocytes, resulting in increased expression of ATG5, Belin1, LC3II, and an increased number of autophagosomes. In addition, cadmium exposure upregulated miR-155 expression, downregulated Rheb mRNA expression, and downregulated the level of protein expression in the Rheb/mTOR signaling pathway in rat hepatocytes. The overexpression of miR-155 followed by cadmium exposure upregulated the level of autophagy in BRL3A cells, whereas miR-155 inhibition had the opposite effect. In addition, miR-155 negatively regulated Rheb. A dual-luciferase reporter assay verified the negative regulatory effect of miR-155 on Rheb targeting. Knockdown of Rheb downregulated cadmium-induced autophagy. Therefore, the Rheb/mTOR signaling can negatively regulate autophagy. The present study demonstrates that miR-155 promotes cadmium-induced autophagy in rat hepatocytes by suppressing Rheb expression.
镉是一种环境污染物，威胁着人类和动物的健康。目前的研究表明，虽然镉诱导的肝毒性损伤与自噬密切相关，但其内在机制尚未阐明。microRNA 在自噬的不同阶段发挥调节作用。在这项研究中，我们研究了 microRNA-155（miR-155）调节镉诱导的大鼠肝细胞（BRL 3A 细胞）和体内肝毒性的机制。我们发现，镉暴露可导致大鼠肝脏损伤，导致肝指数降低，丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和碱性磷酸酶（ALP）活性升高，肝细胞脂肪变性和超微结构损伤。镉暴露还诱导肝细胞自噬，导致 ATG5、Belin1、LC3II 的表达增加，自噬体数量增加。此外，镉暴露上调了 miR-155 的表达，下调了 Rheb mRNA 的表达，并下调了大鼠肝细胞中 Rheb/mTOR 信号通路的蛋白表达水平。miR-155 过表达后再暴露于镉可上调 BRL3A 细胞的自噬水平，而 miR-155 抑制则产生相反的效果。此外，miR-155 负调控 Rheb。双荧光素酶报告基因检测验证了 miR-155 对 Rheb 的负调控作用。Rheb 敲低下调了镉诱导的自噬。因此，Rheb/mTOR 信号可以负调控自噬。本研究表明，miR-155 通过抑制 Rheb 表达促进大鼠肝细胞镉诱导的自噬。
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