Page 29 - Human Bile Acid Metabolism: a Postprandial Perspective

Introduction
Since the discovery that bile acids are ligands for the nuclear farnesoid X receptor
(FXR) and the Takeda G-coupled protein receptor 5 (TGR5), studies in both 2 animals and humans have established that bile acids are metabolic integrators
involved in glucose, lipid, and energy metabolism, particularly in the postprandial
state (1). Several recent reviews have addressed conditions in which TGR5 and
FXR have emerged as new targets for pharmacological agents (2, 3). TGR5
activation has been linked to increased energy expenditure in muscle and brown
adipose tissue, immunosuppressive effects in immune cells, and–perhaps most
importantly in the present context-secretion of intestinal L-cell satiety products
such as peptide YY and the incretin hormone glucagonlike peptide-1 (GLP-1)
(2, 4). FXR activation by bile acidsaffects the expression of multiple key regulatory
genes encoding components of the bile acid synthesis cascade, as well as genes acting
in numerous metabolic pathways (5). Interestingly, a recent study demonstrated
that FXR activation in L cells decreases GLP-1 secretion in response to glucose
(6). Most of the effects of FXR and TGR5 activation have been corroborated in
animal models and to alesser degree in human studies. Alteration of the bile acid
pool has been shown to induce changes of parameters that are part of the metabolic
syndrome (ie, insulin resistance,hyperglycemia, hepatic steatosis, low high-density
lipoprotein cholesterol levels, and cardiovascular risk) (7).
Intriguingly, drugs modulating the enterohepatic circulation of bile acids by binding bile acids in or inhibiting their absorption from the small intestine have been shown to improve glycemic control in patients with type 2 diabetes (T2D) (3, 8). The metabolic effects of bile acids mayinvolve the gut hormone fibroblast growth factor 19 (FGF19), which is released from the terminal ileum upon bile acid-induced FXR activation. FGF19 exerts pleiotropic effects on hepatic bile acid metabolism as well as lipid, protein, and glucose metabolism (9). In light of the predominance of postprandial glycemia in determining overall glycemic control in T2D patients (10), as well as the accumulating evidence that bile acids play an important part in the whole-body response to nutrient ingestion (1), we hypothesized that postprandial bile acid concentrations in T2D patients could reveal a “T2D-bile acidFGF19” phenotype with possible pathophysiological implications. Thus, we performed a characterization of postprandial concentrations of 12 plasma bile acids and FGF19 after various meal stimuli in patients with T2D
Postprandial bile acid concentrations
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