PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online)  2016 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: physres@biomed.cas.cz, www.biomed.cas.cz/physiolres Physiol. Res. 65 (Suppl. 4): S427-S440, 2016 REVIEW Bile Acids, Nuclear Receptors and Cytochrome P450 J. JUŘICA 1,2 , G. DOVRTĚLOVÁ 1 , K. NOSKOVÁ 1 , O. ZENDULKA 1 1 Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, 2 Department of Biochemistry, Faculty of Science, Masaryk University, Brno Received August 13, 2016 Accepted October 13, 2016 Summary This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives. Key words Bile acids • FXR • PXR • Cytochrome P450 Corresponding author O. Zendulka, Department of Pharmacology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Fax: +420 549 493 971. E-mail: zendulka@med.muni.cz Introduction The essential physiological role of bile and bile acids (BA) in digestion is to neutralize chyme and serve as emulsifiers of fat in small intestine. Thanks to their amphiphilic nature, BA are emulsifiers which enable absorption of lipids and lipid soluble vitamins. The production and secretion of bile is regulated by intestinal paracrine hormones cholecystokinin and secretin and moreover autoregulation via negative feedback exists, too. BA and phospholipids stabilize micellar dispersion of cholesterol in the bile and facilitate cholesterol excretion as well as excretion of hydrophobic metabolites of xenobiotics, toxins and metals. In past decade, it has been postulated that bile acids may also regulate lipid and glucose homeostasis, thermoregulation, and immune response (Claudel et al. 2011). Especially the role of BA in immune response is undoubtedly involved in the therapeutic effects of some BA in cholestatic liver diseases (Roma et al. 2011, Buryova et al. 2013). The most common human BA (Fig. 1) are cholic acid (CA), chenodeoxycholic acid (CDCA), in much less proportion also glycocholic acid, taurocholic acid (TCA), lithocholic acid (LCA), deoxycholic acid (DCA), and ursodeoxycholic acid (UDCA). BA and oxysterols are natural ligands of several nuclear receptors (NRs), membrane receptors and regulators of metabolism of lipids and glucose (Chiang 2004, Chiang 2009). At least, some of BA regulate above mentioned pathways via their farnesoid X receptor (FXR) agonistic activity. In particular, FXR agonists probably via production of glucagon-like peptides 1 and 2 increase insulin sensitivity, glucose uptake, and adipogenesis in extrahepatic tissues. Meanwhile, they increase fatty acid oxidation, decrease triglyceride, fatty acid, and cholesterol synthesis in the liver and increase insulin production in beta cells (Camilleri and Gores 2015, Adorini et al. 2012). BA as FXR agonists also decrease https://doi.org/10.33549/physiolres.933512