Carbonic anhydrase 14 protects the liver against the cytotoxicity of bile acids in a biliary bicarbonate umbrella-related manner.

AIMS: The "biliary bicarbonate umbrella" is considered a critical protective mechanism of cholangiocytes against bile acid cytotoxicity. Defects in its function are closely related to various chronic cholangiopathies. Carbonic anhydrase 14 (CAR14) is an important element of normal bicarbonate homeostasis and is highly expressed in liver tissues. This study aimed to explore the effects and mechanism of CAR14 on bile acid cytotoxicity in the liver. MAIN METHODS: In vitro, alterations in the whole transcriptome after Car14 gene silencing were assessed by RNA sequencing, and the expression changes in key factors in the "biliary bicarbonate umbrella" were verified by qRT-PCR and western blotting. In vivo, 7 days after bile duct ligation in Car14 gene knockout and wild-type mice, their serum liver function indicators, liver histopathology, hepatic bile acid composition, and whole hepatic proteomic changes were investigated. KEY FINDINGS: In vitro, the transcriptional alterations induced by Car14 silencing were mainly related to transmembrane transport, including ion exchangers and ion channels that are vital in the "biliary bicarbonate umbrella" such as AE2 and CFTR. In vivo, Car14 knockout induced more severe liver dysfunction, hepatic fibrosis and bile duct lesions, and resulted in increased hepatic bile acid levels and altered bile acid compositions in BDL mice. In response, the uptake and synthesis of bile acids in the liver of Car14 knockout mice were suppressed. SIGNIFICANCE: Our data revealed that CAR14 protects the liver against bile acid toxicity, which might provide a theoretical basis for clinical strategies to prevent or treat bile duct diseases.