Page 71 - Human Bile Acid Metabolism: a Postprandial Perspective

Introduction
BA are increasingly recognized as pleiotropic hormones with effects on glucose and lipid metabolism, in addition to their role as intestinal emulgators [1]. This has led to multiple observations that BA metabolism is altered in metabolic disease such as obesity and type 2 diabetes mellitus [2,3]. Patients with type 2 diabetes mellitus show increased fasting levels of deoxycholic acid (DCA), a secondary BA formed by microbial conversion of cholic acid (CA) [4].
Recently, it was also shown that insulin resistance in healthy human subjects is 4 positively correlated to levels of a certain subset of BA that are hydroxylated at the
12α position (12α-OH BA, i.e. CA and DCA) [5]. It is presently unclear whether
these changes are causally involved in insulin resistance. Roux-en-Y gastric bypass
surgery also increase plasma BA levels. Therefore, BA are putative mediators for the beneficial effects on metabolism and body weight present after bariatric surgery [6].
Primary BA are synthesized from cholesterol in the hepatocyte and subsequently conjugated with glycine (G) or taurine (T), yielding glyco- and tauro-conjugates of CA and chenodeoxycholate (CDCA). Exposure to microbiota in the distal ileum and colon leads to deconjugation and dehydroxylation of CA and CDCA yielding the secondary BA DCA and lithocholic acid (LCA), respectively. Intestinal reabsorption from the intestinal lumen and hepatic extraction from the portal circulation occur through passive and active transport. Subsequently, hepatic return completes the enterohepatic cycle. BA enter the systemic circulation in a pattern of postprandial peaks followed by lows, periodically exposing peripheral tissues to concentrations that may be high enough to activate the Farnesoid X Receptor (FXR) and G-protein-coupled transmembrane BA receptor (GPBAR1/ TGR5) [7-10].
These BA receptors are present on tissues inside and outside the trajectory of the enterohepatic circulation. FXR is a nuclear receptor that regulates BA homeostasis in the liver, amongst others by exerting negative feedback control of bile salt synthesis. In contrast, TGR5 is a transmembrane receptor that is abundantly expressed in the gut, brown adipose tissue (BAT) and skeletal muscle [7,8]. Activation of FXR and TGR5 induces secretion of fibroblast growth factor 19 (FGF19) from enterocytes
Acute dietary weight loss
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