Page 99 - Human Bile Acid Metabolism: a Postprandial Perspective

Short term starvation and bile acid supplementation
either negate an effect on CYP8B1 or may be due to considerable intraindividual variation. Moreover, only small changes in BA levels may be seen after a diet intervention of 2 wk (32), whereas after bariatric surgery beneficial changes in glucose metabolism appeared after changes in BA pool composition (8).
We found positive correlations between gDCA and insulin levels at multiple
postprandial time points in both overnight fasted and 40-h fasted states. TGR5
mediates release of GLP-1 by enteroendocrine L cells in response to stimulation
with BAs (45, 46, 49). GLP-1 can in turn lead to increased insulin release.
Alternatively, activation of TGR5 on human pancreatic beta cells leads to rapid
basal and glucose-dependent insulin secretion in vitro (25). DCA is a secondary
BA that makes up around 30% of the total BA pool in humans, where it is mainly
found in its glycine-conjugated form (5). In patients with type 2 diabetes, the
relative contribution of DCA to the total BA pool is increased (5). This could be 5 interpreted as an adaptive response to counter declining beta cell insulin secretion.
Sato and colleagues (39) showed that gDCA is a particularly strong TGR5 agonist, activating 50% of this receptor at a concentration of 1.18 μM.
Forty hours of fasting actually did increase postprandial GLP-1 concentrations. BAs continue to cycle in the enterohepatic cycle during fasting, but it is unclear if increased luminal stimulation by BAs such as gDCA increased the GLP-1 levels after the 40-h fast, because we did not witness increased BA levels in our peripheral samples. Preclinical work has linked an increase of GLP-1 production to an increase of energy status, i.e., AMPK-dependent regulation of GLP1 expression in L-like cells (21).
Likewise, it may be difficult to explain both the increased basal and postprandial FGF19 concentrations after 40 h of fasting. Here, FGF19 may be high to suppress hepatic BA biosynthesis while starving despite absence of stimuli that would normally induce FGF19 release. 7α-Hydroxy-4-cholesten-3-one (C4) reflects hepatic CYP7A1 activity and, indeed, we found suppressed postprandial C4 levels after 40 h of fasting as seen in other studies where high FGF19 levels lower C4 (13, 41). However, increased basal FGF19 after 40 h of fasting did not result in statistically lower basal C4 concentrations. This may be due to lack of power, insufficient basal FGF19 concentrations to inhibit C4, or different circumstances (i.e., glucose, insulin, and bile acid composition) in the fasted state compared
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