Car14, or carbonic anhydrase XIV, is an enzyme that plays significant roles in multiple physiological processes. It is involved in bicarbonate homeostasis and is highly expressed in various tissues including the liver and neurons. In the liver, it is related to the "biliary bicarbonate umbrella" mechanism, while in the brain, it impacts pH regulation in the perisynaptic microenvironment [1,2,3].

In gene knockout mouse models, Car14 -/- mice showed decreased biliary bicarbonate output, which led to liver fibrosis and cholangiocyte proliferation over time [1]. This indicates Car14's essential role in maintaining normal biliary function and liver integrity. In the hippocampus of Car14 knockout mice, NMDA receptor-dependent afterdepolarizations were enhanced, suggesting that Car14 normally curtails these events by regulating pH around synapses [2]. In vivo, Car14 knockout in bile duct-ligated mice induced more severe liver dysfunction, fibrosis, and bile duct lesions, along with altered bile acid levels and compositions [3].

In summary, Car14 is crucial for biliary bicarbonate output, protection against bile acid cytotoxicity in the liver, and regulation of synaptic pH in the hippocampus. The Car14 knockout mouse models have been instrumental in revealing its role in liver-related diseases such as biliary disorders and fibrosis, as well as in understanding its function in the central nervous system [1,2,3].

References:

1. Zhou, Zhenzhen, Qian, Jiajie, Kini, Archana, Gros, Gerolf, Seidler, Ursula. 2022. Loss of luminal carbonic anhydrase XIV results in decreased biliary bicarbonate output, liver fibrosis, and cholangiocyte proliferation in mice. In Pflugers Archiv : European journal of physiology, 474, 529-539. doi:10.1007/s00424-021-02659-3. https://pubmed.ncbi.nlm.nih.gov/35119514/

2. Makani, Sachin, Chen, Huei-Ying, Esquenazi, Susana, Sly, William S, Chesler, Mitchell. . NMDA receptor-dependent afterdepolarizations are curtailed by carbonic anhydrase 14: regulation of a short-term postsynaptic potentiation. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 32, 16754-62. doi:10.1523/JNEUROSCI.1467-12.2012. https://pubmed.ncbi.nlm.nih.gov/23175829/

3. Qian, Jiajie, Shen, Qianyun, Zhang, Tianfang, Yan, Ren, Chen, Zuobing. 2022. Carbonic anhydrase 14 protects the liver against the cytotoxicity of bile acids in a biliary bicarbonate umbrella-related manner. In Life sciences, 310, 121117. doi:10.1016/j.lfs.2022.121117. https://pubmed.ncbi.nlm.nih.gov/36302497/