Page 17 - Human Bile Acid Metabolism: a Postprandial Perspective

Constitutive Androstane receptor (CAR), the Pregnane X receptor (PXR), the Liver 1 X receptor (LXR) and the vitamin D receptor (VDR) (Li & Chiang, 2012). These
are xenobiotic/endobiotic sensing receptors known to be involved in regulation of
hepatic drug oxidation, conjugation and transport, which has considerable overlap
with bile acid metabolism. The interaction of bile acids with these receptors falls outside of the scope of this thesis.
Most of the metabolically active tissues expressing bile acid receptors are not exposed to their ligands either through bile in the gut lumen or via the portal circulation. So how would they be activated in a physiological setting? As described in the previous section, concentrated bile from the liver and gallbladder flows into the intestinal lumen. After reuptake, they enter the portal circulation, where the liver efficiently extracts bile acids from the portal vein for rehydroxylation, conjugation and resecretion. Notably, a fraction bypasses the liver to enter the systemic circulation, where they can be measured in a postprandial peak, reaching a concentration of approximately 1-20 μmol/L 30 to 90 minutes after a mixed meal (N. F. LaRusso et al., 1978). As a consequence, extra-intestinal tissues are exposed to bile acid concentrations that might be high enough to exert biological effects through their receptors, although peripheral concentrations are much lower compared to portal vein concentrations (N. LaRusso et al., 1974). This is of critical importance in the assessment of the physiological role of bile acids in human energy metabolism, as most of the aforementioned pathways and effects have only been described in the context of supraphysiological stimulation or knock-out rodent models.
Bile acids in obesity and type 2 diabetes mellitus
As discussed in the previous sections, bile acid levels in the enterohepatic and systemic circulation are responsive to nutrient intake, making bile acid receptors ideally positioned in the digestive system to function as postprandial metabolic integrators by sensing and conveying information about nutrient status (Angelin & Bjorkhem, 1977; Sonne et al., 2016). Indeed, impaired bile acid signaling has been implicated in the deranged glucose metabolism of patients with obesity and type 2 diabetes mellitus (DM2). This is illustrated by the altered plasma bile acid concentrations and bile acid pool composition in patients with insulin resistance and DM2 (Brufau et al., 2010; Haeusler et al., 2013). In these patients, plasma bile acid levels are increased compared to healthy controls, in particular cholic
Introduction
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