Interplay Between Bile Acid and GLP-1 Receptor Agonist Signaling Informs the Design of Drugs to Combat Obesity and its Metabolic Complications
- Pp. 20-57 (38)Jessica Felton and Jean-Pierre Raufman
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.