Page 48 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 3
Since the discovery of FXR and TGR5, it has been known that different BAs show a hierarchy in receptor activation [8-11]. Additionally, transmembrane transport and conjugation may modulate activation patterns. Hence, porto-peripheral differences of different BA forms and their conjugation and hydrophobicity profiles may predict FXR and TGR5 activation in gut, liver and peripheral organs. In an observational study, we investigated postprandial transhepatic BA fluxes in conscious pigs before and after a mixed meal (Fig. 1). The pig model has been used for diabetes and metabolic research because of its resemblance to human physiology [12]. The aim of this study was to gain more insight in the postprandial transhepatic BA fluxes and plasma profiles of the different BAs and to predict the potential relevance of BAs for FXR and TGR5 activation. In addition, we analysed human portal and peripheral vein BA profiles to translate the experimental results to relevant human data. These data illustrate that the liver selectively extracts most BAs with high TGR5 affinity, which consequently are typically low in the peripheral circulation.
Materials and methods
Animals
Eleven female cross-bred pigs (20-25 kg, 8-12 weeks old) from a commercial breeder (Rosenbaum Farms, Brenham, TX) were individually housed in galvanized bar runs (2 × 3 m) enriched with straw and toys to acclimatize for 2 weeks before surgical catheter placement. They were kept on a 12 h light–dark cycle (lights on at 7 AM) with a radio turned on during the light period. Environmental temperature was 21–25 °C. The pigs were fed 1 kg/day, Harlan-Teklad Vegetarian Pig/Sow Grower (Harlan laboratories, Indianapolis, IN). Water was available ad libitum. Data on acylcarnitines from this study have been published previously [13]. All animal experiments were approved by the Institutional Animal Care and Use Committee of Texas A & M University, USA.
Surgery
We placed the intravascular catheters one week before the experiment using the surgical techniques described earlier [14,15]. In short, we fasted the animals for 16 h before surgery and sedated them using an intramuscular injection of tiletamine- zolazepam (3.3 mg/kg) (Telazol; Zoetis, Kalamazoo, MI). Animals were intubated
46