For more than a century the physiological role of bile acids was considered
limited to their actions in cholesterol metabolism and lipid absorption from the
gastrointestinal tract. Evidence emerging over the past 20 years has greatly changed
this perspective. It is now apparent that these complex molecules play an integral
signaling function within the gut and have extra-intestinal hormonal actions. Bile acid
interaction with plasma membrane G protein-coupled receptors (e.g. TGR5, M3R) and
nuclear receptors (e.g. FXR) expressed on intestinal epithelial cells modulates postreceptor
signaling and gene transcription. Herein, we review the fundamentals of how
bile acid structure governs the interaction of these molecules with cell receptors and
transport proteins (e.g. ASBT), and how these interactions are important for nutritional
balance. We focus on bile acid interaction with TGR5, a receptor whose activation
stimulates release of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells;
GLP-1, an intestinal incretin, is important for glucose homeostasis. Drugs that mimic
the actions of GLP-1 or retard its degradation are effective treatments for diabetes,
obesity, and their metabolic complications (e.g. non-alcoholic fatty liver disease).
Altered gut and plasma levels of bile acids and GLP-1 are important for the clinical
benefits of bariatric surgery. Hence, there is great interest in developing novel
pharmaceutical approaches to imitate these changes and, in particular, the beneficial
actions of bile acids. We offer a critical analysis of these approaches and propose novel
opportunities for drug design to combat the current obesity epidemic and its metabolic
complications.
Keywords: Bariatric surgery, Bile acids, Bile acid sequestrants, DPP4,
Enteroendocrine L cells, Exenatide, FXR, Gastric bypass, GLP-1, Incretin,
Metabolic syndrome, Non-Alcoholic fatty liver disease, Non-Alcoholic
steatohepatitis, Obesity, Roux-en-Y, Sitagliptin, TGR5, Type 2 diabetes.
