Page 16 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 1
FXR is also found in white adipose tissue (WAT), although its physiological role there is unknown. In vitro, activation of FXR by a specific and potent FXR ligand (INT747) in conjunction with insulin stimulates adipocyte differentiation, suggesting a role in enhancing insulin signaling (Rizzo et al., 2006). In pancreatic beta cells, which express FXR in vivo, glucose-dependent insulin transcription and secretion were increased by activation of FXR in vitro (Renga et al., 2010).
In addition to FXR, bile acids are ligands for the transmembrane receptor Takeda G-coupled protein receptor 5 (TGR5), sometimes referred to as GPBAR1 (Kawamata et al., 2003; Maruyama et al., 2002; Sato et al., 2007; Watanabe et al., 2006), which is involved in metabolic signaling. Bile acids stimulate TGR5 on the luminal membrane of enteroendocrine L-cells to secrete Glucagon-like peptide-1 (GLP-1), a so-called incretin hormone that in turn stimulates glucose-dependent insulin secretion in the pancreatic beta cell (Katsuma et al., 2005). Outside of the enterohepatic circulation, TGR5 is mainly expressed in muscle and brown adipose tissue, though it has not yet been determined whether is has a relevant function in humans. In vitro and in mice, stimulation of TGR5 with bile acids increases resting energy expenditure through increased activation of iodothyronine deiodinase 2, which in turn activates thyroid hormone (Watanabe et al., 2006). In these tissues, insulin sensitivity is increased after TGR5 activation (Thomas et al., 2008; Watanabe et al., 2006). Bile acids may also stimulate insulin release independently from GLP- 1, as TGR5 is expressed in pancreatic beta cells (as well as FXR, as mentioned previously) (Kumar et al., 2012; Renga et al., 2010). Activation of TGR5 on human pancreatic beta cells leads to rapid basal and glucose-dependent insulin secretion in vitro (Kumar et al., 2012).
In addition to these metabolically active tissues, TGR5 is also expressed in macrophages and Kupffer cells, were TGR5 appears to suppress markers of inflammation. In a mouse model of atherosclerosis, activation of TGR5 was protective (Pols et al., 2011), an effect that was lost in TGR5 -/- mice. This effect has been supported by animal and in vitro studies(Keitel et al., 2008)(Ichikawa et al., 2012). This points to a role for bile acid in regulating the postprandial pro-inflammatory state (Meessen et al., 2019).
Besides the two specific bile acid receptors, a number of other nuclear receptors have been described to be activated by bile acid metabolites, notably the
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