Page 47 - Human Bile Acid Metabolism: a Postprandial Perspective

Introduction
Bile acids (BAs) are intestinal lipid solubilizers, facilitating uptake of fats and fat-
soluble vitamins. BAs are synthesised in the liver from cholesterol, conjugated
to either glycine or taurine, and stored in the gallbladder. After a meal, BAs
are released into the intestine and are taken back to the liver via the superior
mesenteric and the portal veins, a very efficient BA transporter system (reviewed 3 in [1]). In the intestine, unconjugated BAs can diffuse passively over the intestinal
border whereas conjugated forms require active transport to be taken up from the intestinal lumen. Active transport from the intestinal lumen is mediated by the apical sodium-dependent BA transporter (ASBT) in the distal ileum. Subsequently, BAs are transported over the basolateral side of the enterocyte via the organic solute transporter (OSTa/OSTb) and enter the liver via the portal vein. The liver clears most BAs from the portal blood via the Na+ taurocholate cotransporting polypeptide (NTCP) which is highly expressed in the liver and has a high affinity for all conjugated BA. NTCP is aided by transporters of the organic anion transporting polypeptide (OATP) family that can transport unconjugated and sulphated BAs. In addition, it is hypothesized that the enzyme microsomal epoxide hydrolase (mEH) can also function as a sodium-dependent BA transporter on the sinusoidal plasma membrane [2]. Hepatic BAs are excreted into the biliary tract via the bile salt export pump (BSEP) on the canalicular membrane.
Most of the BAs recycle in the enterohepatic circulation and only a small amount of BAs appears in the peripheral circulation. This may have important consequences for the presumed metabolic effects of BAs that are mediated by the nuclear farnesoid X receptor (FXR) and the transmembrane Takeda G protein- coupled receptor 5 (TGR5) [3]. FXR regulates liver BA synthesis and metabolism, but can also contribute to glucose and lipid metabolism by stimulating the release of fibroblast growth factor (FGF) 15/19. TGR5 is not only proposed to mediate the effects of BAs on glucagon-like peptide-1 (GLP-1) and insulin release in the gut and pancreas, but also to affect energy expenditure and possibly insulin sensitivity via organs such as muscle or brown adipose tissue [3]. Portal vein and peripheral plasma BA concentrations peak after a meal [4-7]. These observations suggest that BAs are potentially important postprandial signals to modulate metabolic and endocrine regulation in the gut, liver, muscle and fat.
Transhepatic bile acid kinetics
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