Page 46 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 3
Abstract
Background & aims: Bile acids (BAs) play a key role in lipid uptake and metabolic signalling in different organs including gut, liver, muscle and brown adipose tissue. Portal and peripheral plasma BA concentrations increase after a meal. However, the exact kinetics of postprandial BA metabolism have never been described in great detail. We used a conscious porcine model to investigate postprandial plasma concentrations and transorgan fluxes of BAs, glucose and insulin using the para-aminohippuric acid dilution method.
Methods: Eleven pigs with intravascular catheters received a standard mixed-meal while blood was sampled from different veins such as the portal vein, abdominal aorta and hepatic vein. To translate the data to humans, fasted venous and portal blood was sampled from non-diabetic obese patients during gastric by-pass surgery. Results: The majority of the plasma bile acid pool and postprandial response consisted of glycine-conjugated forms of primary bile acids. Conjugated bile acids were more efficiently cleared by the liver than unconjugated forms. The timing and size of the postprandial response showed large interindividual variability for bile acids compared to glucose and insulin.
Conclusions: The liver selectively extracts most BAs and BAs with highest affinity for the most important metabolic BA receptor, TGR5, are typically low in both porcine and human peripheral circulation. Our findings raise questions about the magnitude of a peripheral TGR5 signal and its ultimate clinical application. Abbreviations: BAs, bile acids; ASBT, apical sodium-dependent bile acid transporter; OST, organic solute transporter; NTCP, taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; mEH, microsomal epoxide hydroxylase; BSEP, bile salt export pump; FXR, farnesoid X receptor; TGR5, takeda G protein-coupled receptor 5; FGF, fibroblast growth factor; GLP-1, glucagon-like peptide 1; PAH, para-aminohippuric acid; TCA, trichloroacetic acid; A, abdominal aorta; V, caval vein; R, renal vein; P, portal vein; H, hepatic vein; HQ, hindquarter muscle; PDV, portal drained viscera; SPL, splanchnic compartment; K, kidneys; LC/MS/MS, liquid chromatography tandem mass spectrometry; UDCA, ursodeoxycholic acid; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; HDCA, hyodeoxycholic acid; g, glycine-conjugated; t, taurine-conjugated; LOQ, lower limit of quantification; BMI, body mass index; ANOVA, analysis of variance; AUC, area under the curve; CYP7A1, cytochrome P450 7A1; KO, knock-out; SHP, short heterodimer partner; EC50, half maximal effective concentration.
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