It has been found that the depression of "ileal Fxr-Fgf15 (fibroblast growth factor 15)-hepatic Cyp7a1 pathway" in coordinated with activation of "hepatic Fxr-Shp (small heterodimer partner)-Cyp8b1 pathway" as well as up-regulation of Cyp27a1 expression synergistically promoting the hepatic biosynthesis of chenodeoxycholic acids (CDCAs) that are the potent agonists of Fxr, contribute to the Bsep up-regulation mediated the bile flow restoration to alleviate the cholestasis.
In the liver, the expression of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), increased noticeably in IF patients with cholestasis.
The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression.
Fxr-/-Shp-/- mice exhibited cholestasis and liver injury as early as 3 weeks of age, and this was linked to the dysregulation of bile acid homeostatic genes, particularly cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1).
Inhibition of cholesterol 7alpha-hydroxylase (CYP7A1) by bile acids and inflammatory cytokines provides an important mechanism to protect hepatocytes from bile acid toxicity during cholestasis.
Cyp 7-/- mice lack a functional cholesterol 7alpha-hydroxylase enzyme and develop cholestasis before up-regulation of 27-hydroxycholesterol 7alpha-hydroxylase activity.