Chronic liver injury decreases levels of cerebral carnitine and acetylcarnitine in rats partly due to the downregulation of organic cation transporters OCT1/2 and OCTN2 at the blood-brain barrier

Abstract

Liver failure often causes hepatic encephalopathy, partly due to dysregulation in cerebral energy metabolism. Carnitine and acetylcarnitine play essential roles in energy metabolism by transporting fatty acids from the cytosol into mitochondria, whose transport across the blood-brain barrier (BBB) is primarily mediated by organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs). This study aimed to investigate whether liver injury alters the expression of OCTs and OCTNs at the BBB, leading to decreased cerebral carnitine and acetylcarnitine levels and impaired energy metabolism using thioacetamide-induced chronic liver injury (CLI) in rats. The results showed that CLI significantly downregulated the expressions of OCT1, OCT2, and OCTN2 at the BBB; decreased cerebral carnitine/acetylcarnitine levels; and increased the adenosine diphosphate/ adenosine triphosphate ratio. Elevated plasmic levels of chenodeoxycholic acid (CDCA) and 17β-estradiol (E2) were detected in CLI rats. In hCMEC/D3 cells, E2 downregulated the expressions of OCT2 and OCTN2, which were attenuated by the estrogen receptor-α (ER-α) inhibitor and silencing. CDCA downregulated the expression of OCT1 and OCTN2, which was reversed by the farnesoid X receptor inhibitor and silencing. These in vitro findings were confirmed in rats treated with CDCA or E2. Additionally, HEK-293-OCT1 and HEK-293-OCT2 cells demonstrated an uptake of carnitine and acetylcarnitine, with uptake in HEK-293-OCT2 cells being 6-fold and 14-fold higher, respectively, than in HEK-293-OCT1 cells. In conclusion, thioacetamide-induced CLI downregulated the expressions of OCT1, OCT2, and OCTN2 at the BBB by activating both E2/ER-α and CDCA/farnesoid X receptor pathways, leading to decreased cerebral carnitine and acetylcarnitine levels, disrupted energy metabolism, and contributing to hepatic encephalopathy. SIGNIFICANCE STATEMENT: This study revealed that the deficiency of brain carnitine and acetylcarnitine in thioacetamide-induced chronic liver injury rats is mainly attributed to the downregulation of organic cation transporter 1/2 and organic cation/carnitine transporter 2 expressions at the blood-brain barrier. The increased circulating levels of chenodeoxycholic acid and 17β-estradiol play a significant role in the downregulation of organic cation transporter 1/2 and organic cation/carnitine transporter 2 expression in chronic liver injury.

Keywords: Blood-brain barrier; Chenodeoxycholic acid; Estradiol; Hepatic encephalopathy; Organic cation transporters.