Cyp2c70-KO Mouse

Cyp2c70 is a liver enzyme in rodents. It is responsible for the synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species [1]. Bile acids are crucial for intestinal fat absorption, systemic signaling via receptor-mediated pathways, and cholesterol metabolism [2]. The study of Cyp2c70 using gene knockout (KO) mouse models provides insights into its role in bile acid-related processes.

In Cyp2c70 KO mice, the absence of protective, hydrophilic muricholic acids leads to a more human-like BA composition, resulting in cholestatic liver injury [1]. These mice exhibit increased levels of serum liver injury markers, hepatic inflammation, macrophage infiltration, and biliary cell proliferation [1]. Pharmacological inhibition of the ileal BA transporter (IBAT) can reduce liver damage markers and hepatic gene expression related to immune cell activation and inflammation in Cyp2c70 KO mice [1]. Additionally, Cyp2c70-deficiency in mice profoundly impacts microbiome composition, and the pathophysiological consequences differ between sexes [2]. Female Cyp2c70 -/- mice show more severe and progressive cholangiopathy and fibrosis with age, which can be fully reversed by ursodeoxycholic acid (UDCA) treatment [2]. Perinatal UDCA exposure in Cyp2c70 -/- mice prevents neonatal cholestasis but has no long-lasting effects on liver pathophysiology after treatment discontinuation [3].

In conclusion, Cyp2c70 is essential for the synthesis of muricholic acids in rodents, and its deficiency leads to a human-like bile acid composition and associated liver pathologies. The Cyp2c70 KO mouse models have significantly contributed to understanding the role of this gene in cholestatic liver diseases, the impact of bile acid hydrophobicity, and the evaluation of potential therapeutic interventions such as UDCA treatment and IBAT inhibition [1,2,3].

References:

1. Truong, Jennifer K, Bennett, Ashley L, Klindt, Caroline, Dawson, Paul A, Karpen, Saul J. 2022. Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury. In Journal of lipid research, 63, 100261. doi:10.1016/j.jlr.2022.100261. https://pubmed.ncbi.nlm.nih.gov/35934110/

2. de Boer, Jan Freark, de Vries, Hilde D, Palmiotti, Anna, van de Sluis, Bart, Kuipers, Folkert. 2020. Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid. In Cellular and molecular gastroenterology and hepatology, 11, 1045-1069. doi:10.1016/j.jcmgh.2020.12.004. https://pubmed.ncbi.nlm.nih.gov/33309945/

3. de Vries, Hilde D, Palmiotti, Anna, Li, Rumei, Kuipers, Folkert, de Boer, Jan Freark. 2022. Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids. In Pediatric research, 93, 1582-1590. doi:10.1038/s41390-022-02303-5. https://pubmed.ncbi.nlm.nih.gov/36151295/