A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human BeingsSummary
| Autor: | Veronika Voronova, Kirill Peskov, Victor Sokolov, Amani Al-Khaifi, Chanchal Kumar, Mats Rudling, Gabriel Helmlinger, Sara Straniero, Bo Angelin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Malabsorption OATP organic anion transporting polypeptide Physiology-Based Modeling Gallstones uBA unconjugated bile acid Bile Acids 0302 clinical medicine Small intestinal bacterial overgrowth Enterohepatic Circulation FGF-19 fibroblast growth factor-19 Bile Intestinal Mucosa Enterohepatic circulation tDCA taurine-conjugated deoxycholic acid Farnesoid X Receptor Original Research CA cholic acid Gastrointestinal tract Cholesterol 7α-Hydroxylase Bile acid Chemistry Liver Diseases EHC enterohepatic circulation Gastroenterology Gallbladder gDCA glycine-conjugated deoxycholic acid uCA unconjugated cholic acid Editorial Liver BA bile acid CDCA сhenodeoxycholic acid 030211 gastroenterology & hepatology uCDCA unconjugated сhenodeoxycholic acid Diarrhea uDCA unconjugated deoxycholic acid medicine.medical_specialty Biochemical Phenomena medicine.drug_class NTCP sodium-taurocholate cotransporting polypeptide Models Biological Permeability Bile Acids and Salts 03 medical and health sciences FXR farnesoid X receptor Metabolic Diseases Ileum Internal medicine gCA glycine-conjugated cholic acid tCDCA taurine-conjugated сhenodeoxycholic acid medicine Humans Fibroblast Growth Factor-19 lcsh:RC799-869 tCA taurine-conjugated cholic acid Hepatology gCDCA glycine-conjugated сhenodeoxycholic acid Metabolism CYP7A1 cholesterol 7α-hydroxylase Lipid Metabolism medicine.disease ODE ordinary differential equation 030104 developmental biology Endocrinology DCA deoxycholic acid Intestinal Absorption Farnesoid X receptor lcsh:Diseases of the digestive system. Gastroenterology ASBT apical sodium-dependent bile acid transporter Gastrointestinal Motility Flux (metabolism) |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 1, Pp 149-170 (2020) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background & Aims Disturbances of the enterohepatic circulation of bile acids (BAs) are seen in a number of clinically important conditions, including metabolic disorders, hepatic impairment, diarrhea, and gallstone disease. To facilitate the exploration of underlying pathogenic mechanisms, we developed a mathematical model built on quantitative physiological observations across different organs. Methods The model consists of a set of kinetic equations describing the syntheses of cholic, chenodeoxycholic, and deoxycholic acids, as well as time-related changes of their respective free and conjugated forms in the systemic circulation, the hepatoportal region, and the gastrointestinal tract. The core structure of the model was adapted from previous modeling research and updated based on recent mechanistic insights, including farnesoid X receptor–mediated autoregulation of BA synthesis and selective transport mechanisms. The model was calibrated against existing data on BA distribution and feedback regulation. Results According to model-based predictions, changes in intestinal motility, BA absorption, and biotransformation rates affected BA composition and distribution differently, as follows: (1) inhibition of transintestinal BA flux (eg, in patients with BA malabsorption) or acceleration of intestinal motility, followed by farnesoid X receptor down-regulation, was associated with colonic BA accumulation; (2) in contrast, modulation of the colonic absorption process was predicted to not affect the BA pool significantly; and (3) activation of ileal deconjugation (eg, in patents with small intestinal bacterial overgrowth) was associated with an increase in the BA pool, owing to higher ileal permeability of unconjugated BA species. Conclusions This model will be useful in further studying how BA enterohepatic circulation modulation may be exploited for therapeutic benefits. Graphical abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|