Page 79 - Human Bile Acid Metabolism: a Postprandial Perspective

microbiome and subsequently decreases postprandial plasma DCA levels and peripheral insulin sensitivity [25]. Alternatively, increased activity of the sterol 12α-hydroxylase CYP8B1 would shift de novo BA synthesis towards production of CA, the precursor of microbiota-generated DCA [26]. CYP8B1 is under control of various signals amongst which insulin is a potent suppressor [26]. We cannot exclude the possibility that during the hypocaloric diet insulin sensitivity may have been lower thereby repressing CYP8B1 to a lesser degree.
Interestingly, several studies indicate that obese, insulin resistant subject have
increased fasting levels of DCA [2,4], with one group finding decreased total 4 BA in obese subjects [3]. Brufau and colleagues showed by using stable isotope
tracers that obese patients with type 2 diabetes mellitus exhibit increased
CA synthesis, increased rates of DCA input and consequentially an enlarged
DCA pool [4]. Haeusler et al. expanded this observation to healthy human
subjects. In a large cohort of nondiabetic subjects, insulin resistance assessed by euglycemic-hyperinsulinemic clamp studies was associated with an increase in
fasting levels of 12αOH-BA, to which DCA was the largest contributor [5]. In
a follow-up study, they showed that 12αOH-BA synthesis was preferentially
increased in obese, insulin resistant subjects, leading to higher fasting and peak
levels of total BA [2]. They associated these changes to decreased expression of bile
acid transporters in liver biopsies from patients undergoing Roux-en-Y gastric
bypass, with these bile salt transporters hypothesized to be under acute control
of insulin signaling. In light of these studies, it is counterintuitive that plasma
DCA levels are high in obese and diabetic subjects and increase further after
weight loss. Although we cannot explain this finding, it is likely that activity of BA
transporters, expression of CYP8B1 and the gut microbiome all play a role.
Energy expenditure was decreased by the diet, which is consistent with the large body of literature describing decreased basal metabolism during calorie restriction [22]. BA are thought to be able to increase energy expenditure through activation of TGR5-signaling in myocytes and brown adipocytes. In these cell types, TGR5- activation has been shown to lead to increased expression of type 2 deiodinase, which converts thyroid hormone into its active form [27]. This in turn leads to an increase in thermogenesis, resulting in weight loss. Of the circulating BA, DCA is the most effective ligand for TGR5 with an EC50 of 0.79-1.25 mmol/L depending on conjugation state [12]. In our study, despite DCA levels reaching higher
Acute dietary weight loss
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