Inhibition of bile acids synthesis via fibroblast growth factor 19 (FGF19) through intestinal signaling: A population analysis
Dina Chernikova (1), Victor Sokolov (1), Veronika Voronova (1), Amani Al-Khaifi (2, 3), Sara Straniero (2, 3), Mats Rudling (2, 3), Chanchal Kumar (3, 4), Kirill Peskov (1), Gabriel Helmlinger (5), Bo Angelin (2, 3)
(1) M&S Decisions, Moscow, Russia (2) Metabolism Unit, Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden (3) Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Novum, Huddinge, Sweden (4) Cardiovascular and Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden (5) Quantitative Clinical Pharmacology, IMED Biotech Unit, AstraZeneca, Waltham MA, USA
Objectives: Regulation of bile acid (BA) synthesis is mediated through the farnesoid X receptor (FXR), which is predominantly expressed in the liver and intestine (1). The role of direct interaction of BAs with hepatic FXR versus the influence of FGF19 which is secreted from the small intestine after BA-mediated FXR activation is still unclear (2, 3). Objective of this population analysis was to estimate the possible role of intestinal signaling via FGF19 in the inhibition of BA synthesis.
Methods: Data for analysis was obtained from 11 healthy volunteers under sequential treatment with cholestyramine (CME) (4g QID), CME preceded by atorvastatin (40 mg daily) and without treatment. Statistical analysis was performed using a sample cross covariance function in R and MATLAB, to investigate time correlations of FGF19/7-alpha-hydroxy-4-cholesten-3-one (C4), FGF19/BA and BA/C4. The model describing the functional relationship between FGF19 and C4 was obtained based on an analytical solution of the corresponding system of differential equations.
Results: The analytically-obtained functional relationship between FGF19 and C4 reproduced the central trend and, partially, variability in the observed data. Values of the population parameter estimates revealed an inverse square root dependence of CYP7A1 activity on FGF19. The sample cross-correlation analysis demonstrated the presence of a time lag (up to 3.5 h) between FGF19 synthesis and C4 response. Positive correlations were observed between FGF19 and glycine-conjugated bile acids, GDCA and GCDCA, but not GCA.
Conclusions: The effect of intestinal signaling via FGF19 on the inhibition of BA synthesis can be approximated by an empirical model with an inverse square root dependence of CYP7A1 activity on FGF19. However, additional data are required to improve quality of predictions and allow for further analysis.
References:
[1] T. Claudel, The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism, Arterioscler. Thromb. Vasc. Biol. 25, 2020–2030 (2005).
[2] T. LundåSen, C. GäLman, B. Angelin, M. Rudling, Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man, J. Intern. Med. 260, 530–536 (2006).
[3] M.-H. Xie, I. Holcomb, B. Deuel, P. Dowd, A. Huang, A. Vagts, J. Foster, J. Liang, J. Brush, Q. Gu, K. Hillan, A. Goddard, A. L. Gurney, FGF-19, A NOVEL FIBROBLAST GROWTH FACTOR WITH UNIQUE SPECIFICITY FOR FGFR4, Cytokine 11, 729–735 (1999).
