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.

Effects of Lipolysis-Stimulated Lipoprotein Receptor on Tight Junctions of Pancreatic Ductal Epithelial Cells in Hypertriglyceridemic Acute Pancreatitis

“…Studies have shown that PA can induce endoplasmic reticulum stress [ 19 ], increase activation of NF- κ B [ 21 ] in acinar cells, and induce apoptosis of pancreatic beta cells and mitochondrial dysfunction [ 22 ]. Studies have shown that HTG or PA impairs barrier functions, such as the blood-brain barrier [ 23 ] and intestinal barrier [ 16 , 17 , 24 ] by disrupting the TJ integrity.…”

Long-term maintenance of synaptic plasticity by Fullerenol Ameliorates lead-induced-impaired learning and memory in vivo

“…Lead does not have an effective physiological role in organisms but has numerous harms [ 9 – 11 ]. Because lead can mimic calcium, disrupt tight junctions, increase permeability surface area and induce brain perfusion, it will target the brain vasculature and damage the blood–brain barrier system [ 12 – 14 ]. Lead poisoning may interfere with normal brain development, including blocking synaptogenesis in the cerebral cortex, reducing the number of neurons, depressing neurotransmission and neuronal growth [ 15 ].…”

Neurovascular Dysfunction in Diverse Communities With Health Disparities—Contributions to Dementia and Alzheimer’s Disease

“…Additionally, Alabamians with less education ( Figure 2A ) and low income ( Figure 2B ) were more susceptible to diabetes ( Explore Diabetes in Alabama, 2021 Annual Report). Several studies have shown an association between diet-induced obesity or diabetes with vascular dysfunction ( Chang et al, 2014 ; de Paula et al, 2021 ; Li et al, 2021 ). Excessive caloric consumption stimulates peripheral immune cells, induces the generation of proinflammatory cytokines and increases oxidative stress, which have all been linked to BBB dysfunction ( Salameh et al, 2019 ).…”