Investigating the role of nucleoside reverse transcriptase inhibitors in modulating lipotoxicity: Effects on lipid dynamics stress pathways, and insulin resistance on the function of dopaminergic neurons

Despite decades of advancements in HIV treatment, the persistence of viral reservoirs necessitates lifelong therapy, complicating efforts to fully control the infection. Nucleoside reverse transcriptase inhibitors (NRTIs) remain a cornerstone of HIV treatment, but long-term use is associated with side effects, including lipid metabolism disruption and neurocognitive disorders. There is a gap in understanding the safety of antiretrovirals and their impact on lipid toxicity in the central nervous system. To address this issue, our study investigated the impact of NRTIs, specifically lamivudine and zidovudine, on lipid metabolism and insulin resistance in the SH-SY5Y dopaminergic neuronal cell line. We also compared these effects to those induced by two free fatty acids, palmitic and docosahexaenoic acids. We measured mitochondrial superoxide levels, fatty acid binding proteins 4 and 5, and overall lipid content. Additionally, we assessed insulin resistance by analyzing the phosphorylation of mitogen-activated protein kinases and phosphoinositide 3-kinase, as well as the concentrations of insulin receptor substrate 1 and insulin receptor. The results demonstrated that NRTIs led to reduced fatty acid binding protein 4 levels and lipid content, similar to the effects observed with fatty acids. Moreover, lamivudine and zidovudine increased mitochondrial superoxide levels. Lamivudine also amplified the phosphorylation level of ERK. These findings suggest that NRTIs may contribute to lipotoxicity in dopaminergic neurons, warranting further investigation into their long-term effects on the central nervous system.