Cyp8b1, also known as sterol 12α-hydroxylase, is a unique P450 enzyme crucial for bile acid (BA) metabolism. It catalyzes the 12α-hydroxylation of intermediates in the BA synthesis pathway, determining the ratio of 12α-hydroxylated (12α-OH) to non-12α-OH BAs, and plays a role in the conversion of cholesterol to cholic acid (CA) [3]. This process is integral to lipid metabolism, as BAs are involved in lipid absorption and also act as signaling molecules that can activate cell-signaling receptors [4].

In mouse models, Cyp8b1 deficiency has shown diverse effects. Cyp8b1 knockout mice have improved glucose tolerance, insulin sensitivity, and β-cell function, due to increased GLP-1 secretion resulting from reduced intestinal fat absorption [4]. Downregulation of Cyp8b1 in mice mimics the metabolic improvements seen after vertical sleeve gastrectomy, while its overexpression dampens these benefits [1]. Additionally, Cyp8b1-knockout mice are resistant to colitis, as the absence of CA (synthesized by Cyp8b1) prevents the inhibition of peroxisome proliferator-activated receptor alpha (PPARα), allowing normal fatty acid oxidation and Lgr5+ intestinal stem cell renewal [2].

In conclusion, Cyp8b1 is essential for regulating bile acid composition, which in turn impacts lipid and glucose metabolism, as well as intestinal epithelial repair. The use of Cyp8b1 knockout mouse models has been instrumental in uncovering its role in obesity, diabetes-related glucose metabolism, and colitis, providing potential therapeutic targets for these diseases.

References:

1. Liu, Yanjun, Tu, Jui, Shi, Linsen, Jin, Lihua, Huang, Wendong. 2023. CYP8B1 downregulation mediates the metabolic effects of vertical sleeve gastrectomy in mice. In Hepatology (Baltimore, Md.), 79, 1005-1018. doi:10.1097/HEP.0000000000000627. https://pubmed.ncbi.nlm.nih.gov/37820064/

2. Chen, Li, Jiao, Tingying, Liu, Weiwei, Gonzalez, Frank J, Xie, Cen. . Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal. In Cell stem cell, 29, 1366-1381.e9. doi:10.1016/j.stem.2022.08.008. https://pubmed.ncbi.nlm.nih.gov/36055192/

3. Wang, Yutong, Wang, Yixuan, Hu, YiTing, Zhang, Xinjie, Lan, Ke. 2024. CYP8B1 Catalyzes 12alpha-Hydroxylation of C27 Bile Acid: In Vitro Conversion of Dihydroxycoprostanic Acid into Trihydroxycoprostanic Acid. In Drug metabolism and disposition: the biological fate of chemicals, 52, 1234-1243. doi:10.1124/dmd.124.001694. https://pubmed.ncbi.nlm.nih.gov/39214664/

4. Kaur, Achint, Patankar, Jay V, de Haan, Willeke, Singaraja, Roshni R, Hayden, Michael R. 2014. Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1. In Diabetes, 64, 1168-79. doi:10.2337/db14-0716. https://pubmed.ncbi.nlm.nih.gov/25338812/