Nitroxoline Upregulates LDLR Expression, Enhances Lipid Metabolism, and Reduces Hepatic Steatosis and Atherosclerosis in Apoe-/- Mice

Low-density lipoprotein receptors (LDLRs) are crucial for cholesterol metabolism. Dysregulation of lipid homeostasis can lead to atherosclerosis and contribute to steatohepatitis. This study investigated the effects of nitroxoline on LDLR expression and its protective effects against lipid dysregulation, hepatic steatosis, and atherosclerosis. A comprehensive screening of FDA-approved clinical drugs was conducted to identify candidates capable of modulating LDLR expression. Nitroxoline emerged as a promising agent and was further tested in various assays, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, flow cytometry, and RNA-seq analysis to evaluate the effects on LDLR expression and cholesterol uptake in Huh7 cells. In vivo studies were performed on Apoe-/- mice to assess the impact of nitroxoline on lipid metabolism, hepatic steatosis, and atherosclerosis progression. Nitroxoline significantly upregulated LDLR mRNA and protein levels in Huh7 cells, enhancing LDL uptake and binding. It enhanced SREBF2 by downregulating PPP2CA and stabilized LDLR mRNA through AMPK and JNK signaling pathways. RNA-seq analysis revealed upregulation of genes associated with cholesterol homeostasis and downregulation of genes involved in triglyceride biosynthesis. In Apoe-/- mice, nitroxoline reduced serum levels of total cholesterol, triglycerides, and LDL-C, while not affecting HDL-C levels. Histological analysis showed significantly reduced hepatic steatosis and a tendency to halt atherosclerotic plaque formation in nitroxoline-treated mice. Nitroxoline demonstrates a dual role in upregulating LDLR expression and improving hepatic lipid metabolism. By modulating lipids and providing hepatoprotection, nitroxoline highlights its potential for reducing atherosclerosis and treating lipid-related metabolic disorders.