Page 18 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 1
acid and deoxycholic acid (Haeusler et al., 2013; Brufau et al., 2010). While this relationship is poorly understood, there is some evidence that insulin normally regulates production of cholic acid and deoxycholic acid through the transcription factor Forkhead box protein 1 (FoxO1), which represses Cyp8b1, one of the enzymes responsible for bile acid synthesis (Haeusler et al., 2012). The impaired insulin signaling in DM2 is then thought to lead to increased generation of bile acids.
In contrast, obesity is characterized by decreased postprandial concentrations of bile acids in plasma, while markers of bile acid synthesis were shown to be increased (Glicksman et al., 2010; Haeusler et al., 2016). The blunted postprandial peaks could be attributed to slower intestinal transit in obese subjects, a theory that is underlined by the quick restoration seen in these patients after undergoing Roux-en-Y gastric bypass (RYGB) (Ahmad et al., 2013).
Bariatric surgery on the other hand, RYGB in particular, increases fasting and postprandial plasma bile acid levels, resulting in a complete cure of DM2 in many cases, although if and how these changes are related is presently unclear (Jørgensen et al., 2015; Schauer et al., 2012).
This data from human models of DM2 and obesity suggests that bile acids play a role in modulating the postprandial metabolic response (changes in glucose and lipid metabolism in response to a sudden influx of nutrients) (Lefebvre, Cariou, & Lien, 2009). There seems to be a signaling role in liver, white and brown adipose tissue, pancreas, and in muscle, where the two bile acid receptors are expressed in varying levels of abundance. As discussed above, postprandial plasma bile acid peak concentrations may be high enough to activate these receptors in vivo. Recently, trying to emulate the success of GLP-1 receptor-targeted therapies, TGR5 has been proposed as a pharmacological target to combat obesity and DM2 (Maruyama et al., 2002; Sato et al., 2008; Thomas et al., 2009; Watanabe et al., 2004, 2006). As of the writing of this thesis, this has not yielded any safe and effective compounds.
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