Page 39 - Human Bile Acid Metabolism: a Postprandial Perspective

as recently demonstrated by Morton et al (29). However, in contrast to the data
by Morton et al (29) showing that FGF19 concentrations increase preferentially
in response to carbohydrates as opposed to protein and fat, we found that FGF19 concentrations increased with increasing fat and decreasing carbohydrate content 2 in the meals. Notably, despite some gallbladder contraction after the OGTT (11),
FGF19 concentrations remained more or less at the basal concentration in the NGTgroup and increased slightly in the T2D patients (Figure 1). Thus, although the data by Morton et al (29) indicate that the increase in postprandial FGF19 concentrations involves mechanisms additional to bile acid-induced FXR activation, our data fit with the notion of FXR dependency. However, in our T2D patients, there was a clear dissociation between postprandial concentrations of bile acids and FGF19 (but positive correlations were still demonstrated) compared to NGT subjects, and the “dose-response” relationship between fat (gallbladder contraction) and FGF19 was clearly reduced. This may indicate that bile acid-induced FXR activation is impaired in T2D, leading to decreased secretion of FGF19, which could explain the higher bile acid concentrations because FGF19 inhibits bile acid synthesis (30). Indeed, reduced FGF19 concentrations in T2D patients have been reported in recent clinical studies (31–33). Although mechanisms independent of FXR could be at work in T2D (ie, altered synthesis, secretion, and degradation of FGF19, activation of the pregnane X and vitamin D receptors by bile acids) (7), the enterohepatic bile acid composition is a likely determinant of the degree of FXR activation. However, in our study, CDCA concentrations, the most potent natural ligand of FXR, were unaltered in T2D patients vs NGT subjects, whereas DCA concentrations (a much weaker FXR agonist) were higher along with CA (not an FXR ligand). Such bile acid milieu should, theoretically, favor FXR activation and subsequent FGF19 secretion. However, postprandial UDCA concentrations were slightly higher in T2D patients vs NGT subjects. Although plasma UDCA concentrations were very low, this finding is of interest because UDCA is considered an FXR antagonist (5, 34).
Interestingly, using the murine GLUTag L-cell line, human intestinal biopsies, and different mouse models, Trabelsi et al (6) demonstrated that FXR activation inhibited glycolysis and ATP production, which in turn decreased proglucagon transcription and GLP-1 secretion in response to glucose. In contrast, FXR deficiency or FXR deactivation (using bile acid sequestering agents) promoted GLP- 1 production and secretion (6). Thus, this newly identified FXR/GLP-1 pathway
Postprandial bile acid concentrations
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