Abstract
Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1). We aimed to investigate whether liver failure induced by bile duct ligation (BDL) increases levels of brain AAAs by affecting the expression and function of LAT1. The LAT1 function was assessed using the brain distribution of gabapentin. It was found that BDL significantly increased levels of gabapentin, phenylalanine, and tryptophan in the cortex, hippocampus, and striatum of rats, and upregulated the expression of total LAT1 protein in hippocampus and striatum as well as cortex membrane LAT1 protein. HCMEC/D3 served as in vitro BBB model, and the data showed that both the serum of BDL rats and bilirubin induced LAT1 expression and function, while bilirubin oxidase almost abolished the upregulation of LAT1 protein by bilirubin and the serum of BDL rats. The enhanced function and expression of LAT1 were also observed in the hippocampus and striatum of hyperbilirubinemia rats. Both aryl hydrocarbon receptor (AhR) antagonist α-naphthoflavone and AhR silencing obviously attenuated the upregulation of LAT1 protein by bilirubin or omeprazole. This study provides the first evidence that BDL upregulates LAT1 at the rat BBB, attributed to the activation of AhR by the increased plasma bilirubin. The results highlight the mechanisms causing BDL-increased levels of brain AAAs and their physiological significance.
Highlights
Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1)
Several studies [3,4,5,6,7,8,9,10,11,12,13] have demonstrated that liver failure significantly elevates concentrations of aromatic amino acids (AAAs) in the brain or cerebrospinal fluid, including phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), whose increases are often positively related to grades of hepatic encephalopathy [3,4,6]
The results showed that both omeprazole and unconjugated bilirubin (UCB) remarkably upregulated the expression of LAT1 protein in HCMEC/D3 cells (Figure 3A,B), which could be reversed by α-naphthoflavone (Figure 3A,B)
Summary
Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1). It was found that BDL significantly increased levels of gabapentin, phenylalanine, and tryptophan in the cortex, hippocampus, and striatum of rats, and upregulated the expression of total LAT1 protein in hippocampus and striatum as well as cortex membrane LAT1 protein. Several studies [3,4,5,6,7,8,9,10,11,12,13] have demonstrated that liver failure significantly elevates concentrations of aromatic amino acids (AAAs) in the brain or cerebrospinal fluid, including phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), whose increases are often positively related to grades of hepatic encephalopathy [3,4,6]. The real mechanism by which liver failure increases concentrations of brain AAAs has not been fully investigated
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