Microcystin-RR promote lipid accumulation through CD36 mediated signal pathway and fatty acid uptake in HepG2 cells

Microcystins (MC)-RR is a significant analogue of MC-LR, which has been identified as a hepatotoxin capable of influencing lipid metabolism and promoting the progression of liver-related metabolic diseases. However, the toxicity and biological function of MC-RR are still not well understood. In this study, the toxic effects and its role in lipid metabolism of MC-RR were investigated in hepatoblastoma cells (HepG2cells). The results demonstrated that MC-RR dose-dependently reduced cell viability and induced apoptosis. Additionally, even at low concentrations, MC-RR promoted lipid accumulation through up-regulating levels of triglyceride, total cholesterol, phosphatidylcholines and phosphatidylethaolamine in HepG2 cells, with no impact on cell viability. Proteomics and transcriptomics analysis further revealed significant alterations in the protein and gene expression profiles in HepG2 cells treated with MC-RR. Bioinformatic analysis, along with subsequent validation, indicated the upregulation of CD36 and activation of the AMPK and PI3K/AKT/mTOR in response to MC-RR exposure. Finally, knockdown of CD36 markedly ameliorated MC-RR-induced lipid accumulation in HepG2 cells. These findings collectively suggest that MC-RR promotes lipid accumulation in HepG2 cells through CD36-mediated signal pathway and fatty acid uptake. Our findings provide new insights into the hepatotoxic mechanism of MC-RR. MC-RR exposure promotes up-regulation of CD36 and activates the AMP-activated protein kinase (AMPK) and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, resulting in a significant augmentation of cellular triglycerides (TG), total cholesterol (T-CHO), phosphatidylethanolamine (PE), and phosphatidylcholine (PC), thus driving the observed lipid accumulation. [Display omitted] •Low concentration of MC-RR retains cell viability but promotes lipid accumulation.•MC-RR leads to augmentation of triglycerides, total cholesterol, phosphatidylethanolamine, and phosphatidylcholine.•MC-RR exposure induces significant up-regulation of CD36.•MC-RR activates AMPK and PI3K/AKT/mTOR pathway.