Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms

Abstract

Background The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier. Methods Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestatic rats, or bile acid treatment, in the presence of a Rac1 inhibitor. Results Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability. Conclusions These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions.

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

“…However, Faropoulos et al have reported that BDL time-dependently down-regulates occludin expression in the brains of rats [35] . Another study has demonstrated that BDL impairs the BBB integrity of rats, as evidenced by increased brain extravasation of Evans Blue [44] . The reason for this discrepancy is unclear, but it might be related to the duration of HE or animal strains and remains to be further explored.…”

“…Serum from experimental animals has been used to investigate the effects of pathological factors in in vitro cell models, such as rat brain microvessel endothelial cells [44] and human endothelial cells [45] . In this study, the effects of serum from BDL rats on the function and expression of BCRP were also investigated by using HCMEC/D3 cells, a human cerebral microvascular endothelial cell line.…”

Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

“…24,25 Once again, at the time when minor neurological symptoms were evident, mice were anesthetized and transcardially perfused with ice-cold saline to remove the blood from the brain and the amount of fluorescence in homogenates of the frontal cortex was assessed as previously described. 26 …”

“…26,37,53e56 Furthermore, we have recently demonstrated that the circulating bile acids themselves can induce permeability in the BBB via a mechanism involving the Rac1-dependent phosphorylation of the tight junctioneassociated protein Occludin1. 26 The exact mechanisms that lead to bile acid entry into the brain during HE, whether through alterations in bile acid transporters in the choroid plexus or increased passive diffusion through a leaky BBB, are unclear and are areas of ongoing research in our laboratory.…”

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

“…Increased serum bile acids have been implicated in the increased blood-brain barrier permeability observed in a rat model of chronic liver disease [28] hereby allowing access of bile acids and other signaling molecules to the brain. Furthermore, increased bile acid content in brain tissue has been demonstrated in rodent models of both acute and chronic liver diseases [26,27].…”