Page 87 - Human Bile Acid Metabolism: a Postprandial Perspective

Short term starvation and bile acid supplementation
Introduction
Bile acids (BA) are known for their role in hepatobiliary cholesterol secretion (37) and detergent properties that enable enteral lipid uptake (28). Recently, BAs have gained interest for their role as hormone-like mediators involved in energy metabolism (33). Their effects are mainly mediated by the nuclear Farnesoid X Receptor (FXR) and the transmembrane Takeda G-protein-coupled receptor (TGR5) (24, 33). BA dynamics in the enterohepatic and systemic circulation are responsive to nutrient intake, and BA receptors are ideally positioned in the digestive system to function as postprandial metabolic integrators by sensing and conveying information about nutrient status (2, 43).
The two main primary human BAs, cholic acid (CA) and chenodeoxycholic
acid (CDCA), are synthesized from cholesterol in the hepatocyte, conjugated 5 with either glycine or taurine, and subsequently stored in the gallbladder. After
a meal, these BAs facilitate the absorption of lipids and lipid soluble vitamins.
The microbiota in the gut are involved in BA deconjugation and dehydroxylation,
yielding the secondary BAs deoxycholic acid (DCA) and lithocholic acid from
CA and CDCA, respectively. BA reabsorption occurs primarily through active
transport in the ileum, and BAs reach the liver via the portal vein (26, 28, 44). A
fraction of BAs escapes hepatic clearance and enters the systemic circulation in a
pattern of postprandial peaks that may be high enough to activate BA receptors in
the systemic circulation (9).
TGR5 is expressed by entero-endocrine L-cells in the intestine, and its activation by BAs results in the release of the incretin glucagon-like peptide 1 (GLP-1) (45). GLP-1, in turn, increases glucose-dependent insulin release from the pancreatic beta cells. BAs may also directly stimulate insulin release, as both FXR and TGR5 are expressed by the beta cell (25, 38). During enterohepatic BA cycling, FXR activation induces a negative feedback loop comprising ileal fibroblast growth factor 19 (FGF19) that represses hepatic BA production.
FGF19 has been suggested to inhibit gluconeogenesis and hepatic lipogenesis, whereas it stimulates glycogen synthesis (22, 36). In contrast, it was recently shown in rodents that FXR is an activator of fasting hepatic gluconeogenesis (35). In humans, administration of a FGF19 analog diminished liver fat without effects on plasma glucose levels (7, 18).
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