Page 172 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 9
Bile acid signals in the portal and systemic compartments
As we describe in Chapter 3, postprandial bile acid concentrations in portal blood are circa five- to tenfold higher than in venous blood due to efficient hepatic extraction. In particular, conjugated versions of the strong TGR5 agonists lithocholic acid (LCA) and hyodeoxycholic acid (HDCA, a secondary bile acid specific to pigs, comparable to the human deoxycholic acid (DCA)) are cleared more efficiently than unconjugated bile acids and chenodeoxycholic acid (CDCA), which has weak affinity for TGR5 (Sato et al., 2008b). This again raises questions whether the TGR5-activating signal in the systemic compartment is meaningful in normal physiology. It has been suggested that supraphysiological stimulation of TGR5 with 15 mg/kg oral CDCA increases energy expenditure in vivo, an effect that is traceable to increased glucose uptake by brown adipose tissue (Broeders et al., 2015). In this study, CDCA concentrations of 12 mmol/L were reached, representing a concentration around five- to tenfold higher than that normally seen after a meal, though this is subject to interindividual variability. In our study with gDCA (Chapter 5), we did not see an increase in resting energy expenditure after a single dose of 750 mg gDCA, which was around 10 mg/kg. Interestingly, gDCA levels in venous blood were only modestly raised, to a peak level of ~1.4 mmol. This suggests that the oral gDCA was hepatically cleared, foregoing direct effects outside of the enterohepatic circulation. This is in line with our finding that unconjugated bile acids pass the liver barrier more easily than conjugated bile acids, making them more suitable to target the systemic compartment.
Future perspectives
Bile acids and their downstream effectors remain a promising area of potential treatment in DM2, obesity and liver disease. However, before potential treatments can be implemented, more research into basic human bile acid metabolism is needed. As referred to in this thesis, the relation between bile acid pool changes in metabolic disease and development of metabolic impairment has so far not been solved. The direction of causality in particular needs to be identified: how is bile acid metabolism affected by metabolic disease, or are bile acid changes a link in the chain of events leading from obesity to hyperlipidemia and insulin resistance and eventually full-blown DM2?
A compounding factor is the efficient negative feedback-inhibition loop of bile acids on their own synthesis via FXR and FGF19, which makes the system
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