Cyp7a1-flox Mouse

Cyp7a1, also known as cholesterol 7α-hydroxylase, is a rate-limiting enzyme in bile acid synthesis [3,4,5]. It plays a crucial role in maintaining cholesterol homeostasis by converting cholesterol into bile acids, which are important for cholesterol metabolism, lipid and lipid-soluble vitamin absorption, bile flow, and gut microbiome regulation [1]. Bile acid synthesis via Cyp7a1 is involved in pathways such as the farnesoid X receptor (FXR)-dependent pathways, including FXR/small heterodimer partner (SHP) and FXR/fibroblast growth factor (FGF)-19/fibroblast growth factor receptor (FGFR)-4 pathways [3]. Genetic models, like mouse models, are valuable for studying Cyp7a1.

In a study generating female mice lacking Cyp7a1 and Cyp27a1 (double knockout, DKO), BA concentrations in serum, liver, gallbladder, and small intestine were significantly reduced compared to wild-type (WT) mice. Despite low BA levels, DKO mice had a similar expression pattern to WT mice for genes involved in BA regulation, synthesis, conjugation, and transport, and also responded similarly to FXR activation by a synthetic FXR agonist [1]. In another study, inhibition of PCSK9 in mice activated PPARα-mediated Cyp7a1 expression, which promoted the conversion of cholesterol into BAs, preventing and alleviating cholesterol gallstones [2].

In conclusion, Cyp7a1 is essential for bile acid synthesis and cholesterol homeostasis. Gene-knockout mouse models, such as the Cyp7a1-and Cyp27a1-deficient female mice and the PCSK9-inhibited mice, have revealed its role in bile acid-related diseases like intrahepatic cholestasis of pregnancy and cholesterol gallstones, contributing to our understanding of these disease mechanisms and potentially providing new therapeutic targets.