Page 171 - Human Bile Acid Metabolism: a Postprandial Perspective

are not the result of an increase in bile acid levels outside of the enterohepatic circulation. Of course, the insulin insensitivity of obesity and DM2 may not arise from the same pathways as fasting-induced insulin resistance (Soeters et al., 2012).
The lack of an effect of short-term fasting on bile acid concentrations also denotes that the relationship between insulin resistance and bile acids as seen in obesity and DM2 likely develops over a longer period of time. This is additionally supported by our own results after placement of the duodenal-jejunal bypass liner (DJBL), where beneficial effects on insulin and glucose levels predate the massive changes in bile acid metabolism, as well as reports by other authors (Dutia et al., 2015; Haeu et al., 2015; Kohli et al., 2013; Patti et al., 2009). This fits with the concept of a bile acid pool that is constantly efficiently being recycled (as we also demonstrated in chapter 3), only showing gradual change after several cycles when the underlying deconjugation and rehydroxylation apparatus is adjusted. Alternatively, changes in the bile acid pool could occur immediately after placement, but not become apparent until hepatic deconjugation and clearance is overwhelmed, leading to increased peripheral plasma bile acid levels. This is supported by the increase in GLP-1 and FGF19 seen immediately after placement of the DJBL, which suggests that bile acid signaling within the enterohepatic circulation is increased, even though peripheral bile acid levels are (still) low (Kaválková et al., 2016).
Recent papers have described increased synthesis of 12α-hydroxylated bile acids in
insulin resistant human subjects (Haeusler et al., 2013; Legry et al., 2017). In mice,
decreased insulin signaling leads to reduced activity of the transcription factor
FoxO1, which normally represses Cyp8B1. The subsequent increase in Cyp8B1
activity then leads to a bile acid pool more skewed to 12α-hydroxylated subtypes,
which have less affinity for FXR (Haeusler et al., 2012). The authors of this finding 9 speculate that this leads to a decrease in FXR-activation and a subsequent increase
in triglyceride levels, linking bile acid pool changes to the dyslipidemia that is characteristically seen in DM2. We were unable to show any significant changes in the 12α-hydroxylated subfraction of bile acids in our studies. This is most likely explained by the timescale involved for changes in hepatic insulin sensitivity to translate to changes in the bile acid pool measurable in peripheral plasma.
Discussion and future perspectives
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