High‐fat diet exacerbates lead‐induced blood–brain barrier disruption by disrupting tight junction integrity

Abstract Environmental exposure to lead (Pb) can damage to the central nervous system (CNS) in humans. High‐fat diet (HFD) also has been suggested to impair neurocognitive function. Blood–brain barrier (BBB) is a rigorous permeability barrier for maintaining homeostasis of CNS. The damage of BBB caused by tight junctions (TJs) disruption is central to the etiology of various CNS disorders. This study aimed to investigate whether HFD could exacerbate Pb exposure induced the destruction of BBB integrity by TJs disruption. To this end, we measured cell viability assay, trans‐endothelial electrical resistance assay, horseradish peroxidase flux measurement, Western blot analysis, and immunofluorescence experiments. The results showed that palmitic acid (PA), the most common saturated fatty acid found in the human body, can increase the permeability of the BBB in vitro which formed in bEnd.3 cells induced by Pb exposure, and decrease the expression of TJs, such as zonula occludins‐1 (ZO‐1) and occludin. Besides, we found that PA could promote the up‐regulation of matrix metalloproteinase (MMP)‐9 expression and activate the c‐Jun N‐terminal kinase (JNK) pathway induced by Pb. MMP‐9 inhibitor or JNK inhibitor could increase BBB integrity and up‐regulate the expressions of ZO‐1 and occludin after treatment, respectively. Moreover, the JNK inhibitor could down‐regulate the expression of MMP‐9. In conclusion, these results suggested that HFD exacerbates Pb‐induced BBB disruption by disrupting TJs integrity. This may be because PA promotes the activation of JNK pathway and then up‐regulated the expression of MMP‐9 after Pb‐exposure. It is suggested that people with HFD exposed to environmental Pb may cause more serious damage to the CNS.