Determination of the role of palmitic acid in cerebral vascular endothelial cell metabolism and effects of palmitic acid-rich diet on cognitive impairment in CBL57/J6 mice

Obesity is a rapidly increasing global issue that can lead to metabolic disorders and neurodegenerative diseases (ND). Research shows a correlation between increased body mass index (BMI) and ND. High BMI levels can cause damage to the blood-brain barrier (BBB) and elevated levels of palmitic acid (PA) in the bloodstream. To investigate the effects of a high palmitic acid diet (HPD) on the BBB, we conducted a study where we performed a moderate traumatic brain injury (TBI) on CBL57/J6 mice as a BBB injury model. We fed the mice an HPD diet cyclically before and after the injury to determine if the damage was permanent and to examine any cognitive effects. We also conducted in vitro studies on brain microvascular endothelial cells to elucidate the molecular cell metabolism of PA. We used the AICAR+L-carnitine model for the first time as a TBI model in cell culture. Furthermore, we conducted in silico studies to identify possible unknown molecular targets of palmitic acid. Our findings indicated that palmitic acid damaged the BBB by disrupting the metabolism of endothelial cells. Molecular docking studies confirmed that palmitic acid has a high binding affinity to the 11β-HSD1 enzyme. Moreover, we found that the damage was permanent in HPD-fed mice as they could not perform the angiogenesis required for the repair response of endothelial cells after TBI. Our in vitro and in vivo studies revealed that PA increased the expression of the 11β-HSD1 enzyme. We screened 7900 FDA-approved drugs on 11β-HSD1 and discovered new potential 11β-HSD1 suppressor drugs through drug repurposing. Our study suggests that the 11β-HSD1 enzyme can be targeted to prevent ND and BBB damage.