Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy.
Biomolecules. 2023 Dec 7;13(12):1758. doi: 10.3390/biom13121758.
(1) Background: Cadmium (Cd) is a potentially toxic element with a long half-life in the human body (20-40 years). Cytotoxicity mechanisms of Cd include increased levels of oxidative stress and apoptotic signaling, and recent studies have suggested that these aspects of Cd toxicity contribute a role in the pathobiology of non-alcoholic fatty liver disease (NAFLD), a highly prevalent ailment associated with hepatic lipotoxicity and an increased generation of reactive oxygen species (ROS). In this study, Cd toxicity and its interplay with fatty acid (FA)-induced lipotoxicity have been studied in intestinal epithelium and liver cells; the cytoprotective function of melatonin (MLT) has been also evaluated. (2) Methods: human liver cells (HepaRG), primary murine hepatocytes and Caco-2 intestinal epithelial cells were exposed to CdCl before and after induction of lipotoxicity with oleic acid (OA) and/or palmitic acid (PA), and in some experiments, FA was combined with MLT (50 nM) treatment. (3) Results: CdCl toxicity was associated with ROS induction and reduced cell viability in both the hepatic and intestinal cells. Cd and FA synergized to induce lipid droplet formation and ROS production; the latter was higher for PA compared to OA in liver cells, resulting in a higher reduction in cell viability, especially in HepaRG and primary hepatocytes, whereas CACO-2 cells showed higher resistance to Cd/PA-induced lipotoxicity compared to liver cells. MLT showed significant protection against Cd toxicity either considered alone or combined with FFA-induced lipotoxicity in primary liver cells. (4) Conclusions: Cd and PA combine their pro-oxidant activity to induce lipotoxicity in cellular populations of the gut-liver axis. MLT can be used to lessen the synergistic effect of Cd-PA on cellular ROS formation.
(1) 背景：镉（Cd）是一种具有长半衰期（20-40 年）的潜在毒性元素。Cd 的细胞毒性机制包括氧化应激和凋亡信号的增加水平，最近的研究表明，Cd 毒性的这些方面在非酒精性脂肪性肝病（NAFLD）的病理生物学中发挥作用，NAFLD 是一种与肝脂肪毒性和活性氧（ROS）生成增加相关的高度流行疾病。在这项研究中，研究了 Cd 毒性及其与脂肪酸（FA）诱导的脂毒性之间的相互作用在肠上皮细胞和肝细胞中的作用；还评估了褪黑素（MLT）的细胞保护功能。(2) 方法：在油酸（OA）和/或棕榈酸（PA）诱导脂毒性之前和之后，将人肝细胞（HepaRG）、原代鼠肝细胞和 Caco-2 肠上皮细胞暴露于 CdCl，在一些实验中，FA 与 MLT（50 nM）联合治疗。(3) 结果：CdCl 毒性与 ROS 诱导和两种肝和肠细胞活力降低有关。Cd 和 FA 协同诱导脂滴形成和 ROS 产生；与 OA 相比，PA 在肝细胞中产生更高的 ROS，导致细胞活力降低，尤其是在 HepaRG 和原代肝细胞中，而 CACO-2 细胞对 Cd/PA 诱导的脂毒性的抵抗力高于肝细胞。MLT 单独或与 FFA 诱导的脂毒性联合使用时，对原代肝细胞中的 Cd 毒性均具有显著的保护作用。(4) 结论：Cd 和 PA 结合其促氧化剂活性在肠道-肝脏轴的细胞群体中诱导脂毒性。MLT 可用于减轻 Cd-PA 对细胞 ROS 形成的协同作用。
