Page 15 - Human Bile Acid Metabolism: a Postprandial Perspective

increases solubility, aiding secretion into bile fluid. Though intestinal bacteria 1 deconjugate bile acids, the majority of the human bile acid pool (around 80%) is
in its conjugated form throughout the enterohepatic cycle (Hofmann & Hagey, 2008).
Bile acids are preferentially conjugated to taurine by bile acid coenzyme A:amino acid N-acyltransferase (BAAT), but as taurine is less prevalent in the human diet, the human
bile acid pool is predominantly glycine-conjugated (Hardison & Grundy, 1983).
Taking into account the steps of synthesis, conjugation to amino-acids, dehydroxylation by bacteria to secondary bile acids, a certain degree of rehydroxylation in hepatocytes and loss in the feces, it is easy to understand that the resulting mixture of bile acids, which we call the bile acid pool, is a variable entity, both within and between individuals and species (Lefebvre, Cariou, Lien, et al., 2009). To compound these differences, different bile acid species and conjugation states impart differences in hydrophilicity and affinity for the various bile acid receptors (Parks et al., 1999; Sato et al., 2008). This may have consequences for their proposed effects on biological processes and translation of preclinical findings to therapeutic settings, as described in this thesis.
Bile acids as metabolic hormones
The traditional view of bile acids as enteral detergents was upended when, in 1999, it became evident that bile acids are ligands for the (until then) orphan nuclear receptor farnesoid X receptor (FXR), exerting negative feedback on their own biosynthesis (Parks et al., 1999). Activation of FXR was shown to suppress transcription of the CYP7A1 gene and thereby expression of cholesterol 7α-hydroxylase, which is the rate-limiting enzyme of bile acid synthesis (Lefebvre, Cariou, & Lien, 2009). In the distal ileum, activation of FXR in enteroendocrine L-cells induces increased expression and secretion of ileal Fibroblast Growth Factor 19 (FGF19). FGF19 is an enterokine that in turn represses hepatic bile acid production through the FGF-receptor-4 (FGFR4) by inhibiting CYP7A1, creating a negative feedback loop (Schaap et al., 2014). Besides this established pathway, FGF19 has also been implicated in regulation of metabolism. Transgenic mice overexpressing FGF19 or treated with an FXR ligand are resistant to diet-induced obesity and insulin resistance (Tomlinson et al., 2002)(Renga et al., 2010). In mice, FGF19 represses genes involved in gluconeogenesis and lipogenesis, instead stimulating fatty acid oxidation and glycogen synthesis (Kir et al., 2011; Potthoff et al., 2011; Schaap et al., 2014).
Introduction
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