Melatonin as a Repairing Agent in Cadmium- and Free Fatty Acid-Induced Lipotoxicity

Abstract

(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 CdCl2 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: CdCl2 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.

Biomarkers of Oxidative and Radical Stress

“…Melatonin demonstrated its utility as a cytoprotective agent, having specific molecular mechanisms involving ERK1/2 agonism, halting cell signaling via the MAPK-ERK1/2 pathway and SAPK activation in the hepatic cell line. Cd and fatty acids induced the accumulation of cellular lipids, whereas MLT lessened the cell death induction effects both in HepaRG and CACO-2 cell lines [23]. These results should encourage further pre-clinical and clinical studies on using MLT as an antioxidant intervention option in the context of Cd exposure.…”

“…Another article in this Special Issue focuses on the toxic effects of cadmium (Cd) as a potentially toxic element (PTE) deriving from pollution or industrial processes that humans can be involved with, thus causing a human health concern and the need for individuating a good antioxidant treatment [23]. In particular, liver cells are targets of Cd-induced oxidative stress, especially when this element is combined with the exposure of free fatty acids, which are known as the main compounds processed in liver cells.…”