Page 101 - Human Bile Acid Metabolism: a Postprandial Perspective

Short term starvation and bile acid supplementation
Contrary to our expectations, we did not detect an effect of oral gDCA on energy expenditure in this study, despite observing significantly increased gDCA plasma concentrations at the end of the meal. TGR5/DIO2 coexpression has been confirmed to be present in both human skeletal muscle myoblasts and brown adipose tissue in humans, suggesting that this pathway is functionally active (4). Broeders et al. (4) described a 5% increase in early morning basal metabolic rate in response to two consecutive doses of unconjugated CDCA given over the course of 24 h. Despite the fact that unconjugated CDCA is a BA with weaker TGR5 affinity compared with gDCA, the increased brown adipose tissue activity was attributed to TGR5 activation (39).
Our study had a few limitations. First, the experiments were designed to assess
acute effects of BAs mediated by TGR5 and not by changes in FXR stimulation or
changes to the composition of the circulating BA pool. Plasma BA concentrations 5 are probably not under short-term regulation but instead are a function of their
portal concentration and a relatively constant hepatic uptake (27). However, longer
duration of BA supplementation may lead to more profound changes in the BA
pool and downstream targets, including prolonged TGR5 and FXR activation (10,
48). Another limitation of this study was the high interindividual variability of BA
curves, which is a recurring finding in postprandial BA studies (14, 47) and may
warrant the inclusion of a larger number of subjects. Also, the results of experiment 1
may be affected by the rate of stomach emptying, which is slower after a 40-h fast (6).
Finally, we were not able to measure portal vein concentrations of the substrates and
hormones of interest, and peripheral sampling may not provide optimal information
about changes within the enterohepatic cycle during our studies (9).
In this study, we show the different effects of 40 h fasting and gDCA administration on BAs and their downstream targets GLP-1 and FGF19. Unexpectedly, 40 h fasting increased both GLP-1 and FGF19, where the former appeared BA independent and the latter BA dependent. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by BAs.
Grants
This research was supported by the Dutch Diabetes Research Foundation [Grant No. 2011.80.1423].
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