Page 62 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 3
(Fig. 7) [11]. This superficial approach does not take into account the shape and range of linearity of the concentrationeactivation curve and the resulting measure overestimates TGR5 activity since BA concentrations were below their EC50 value. However, it shows that TGR5 activation potential may be much higher in the portal vein than elsewhere, most likely because concentrations are also much higher in the portal vein. Interestingly, calculated human TGR5 activation capacities were not different from pigs, whereas the pool composition is very different. This could be explained by the fact that pigs had higher concentrations of BAs, including LCA, and thus similar TGR5 signalling.
Postprandial BAs have been studied to a limited extend, however this is the most sizable study so far in terms of postprandial time points, number of animals/ humans and number of individual LC/MS/MS BAs analyses [7]. We did not perform activating calculations for FXR since the necessary data are not uniformly published for this receptor [8,35]. Alternatively, a more uniform hydrophobicity index has been used to qualify BAs, but these data are not available for all BAs [36-38]. In addition, FXR is located in the nucleus, which complicates the calculation of potential FXR activation with plasma BA concentrations even more.
Our study has strengths and weaknesses. The porcine model is suitable for diabetes and metabolic research because it mimics human physiology and pathophysiology in many respects [12]. More importantly, the pig has a dayenight rhythm comparable to humans, is omnivorous and its intestinal transit time and efficiency of digestion resemble that of humans [39]. In an effort to translate the porcine data to humans, we included healthy obese subjects undergoing bariatric surgery. Fasting plasma BA concentrations are not different in obese subjects despite lower postprandial concentrations [40,41]. BMI is positively correlated to total BA concentrations and markers for hepatic BA synthesis in plasma [41,42]. So the human data presented in this study may alter from (postprandial) BA metabolism in lean subjects. Our speculation that TGR5 activation is greater within the entero-hepatic cycle would greatly benefit from additional measurements in the pigs such as plasma GLP-1 concentrations since intestinal TGR5 activation triggers release of GLP-1 [43]. In addition, FGF19 concentrations would be interesting to indicate activation of the FXR-FGF19 axis and its beneficial effects on liver metabolism [43]. Unfortunately, the numerous blood samples limited the amount of blood per sample. Feeding pigs via a gastric tube may have prevented a normal postprandial hedonic response, but the amount and composition of the meal still elicited a robust physiological
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