Page 168 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 9
The foundation of the present thesis is the relatively underexplored notion that bile acids may act as endocrine hormones through the receptors Takeda G protein-coupled receptor 5 (TGR5) and Farnesoid X Receptor (FXR) in human metabolism. The experimental studies described here address three important topics in the current understanding of human (and porcine) bile acid biology, namely natural variation, response to metabolic challenges and enterohepatic versus systemic effects. We chose to investigate postprandial bile acid metabolism in different metabolic states and to modulate the postprandial bile acid response using interventions aimed at energy metabolism.
Bile acids as systemic postprandial signals
Bile acids and bile alcohols likely arose from the need of early vertebrates to excrete cholesterol in a water-soluble form in a watery environment. They are structurally diverse molecules in vertebrate biology, differing in the number and orientation of hydroxyl subgroups on the sterol backbone, and are instrumental in absorbing lipid-soluble nutrients (Hofmann, 2009). Two specific bile acid receptors have been described, namely FXR and TGR5, with differing affinity for each individual bile acid subtype, as well as the non-specific nuclear receptors Constitutive Androstane Receptor (CAR), Vitamin D Receptor (VDR), Liver X Receptor (LXR) and Pregnane X Receptor (PXR) (Lefebvre et al., 2009). While both FXR and TGR5 have been found to be heavily involved in feedback regulation of bile acid metabolism, their role in human energy metabolism remains underexplored. They are found outside of the enterohepatic tissues, and have been shown to interact with glucose, energy and lipid metabolism in human and rodent models of metabolic disease, but whether they play a relevant part is so far unknown (for a further discussion of the underlying evidence, see chapter 8). While peripheral plasma levels do peak to levels shown to activate these receptors (Sato et al., 2008a), it remains in question whether these are relevant signals in human physiology. In chapter 5 of this thesis, we have described trends and significant correlations at multiple timepoints postprandially between bile acids (in particular the secondary bile acid glycodeoxycholic acid, gDCA) and both GLP-1 and insulin levels. This suggests that the postprandial increase in GLP-1 is at least in part explained by enteral stimulation of TGR5 by bile acids, as previously described by Kuhre and colleagues (Kuhre et al., 2018). In addition, supraphysiological stimulation with gDCA also led to an increase in early postprandial levels of GLP-1, further supporting this notion. This could be a direct effect of gDCA on enteroendocrine
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