Page 145 - Human Bile Acid Metabolism: a Postprandial Perspective

Introduction
Reducing postprandial hyperglycaemia is one of the main goals of modern diabetes therapy. Strategies that increase the postprandial anabolic response, such as short- acting insulin analogue therapy, have been shown to reduce HbA1c and long-term complications of the disease. Trying to emulate the success of therapies that target the glucagon-like peptide-1 (GLP-1) receptor, other G protein-coupled receptors have been suggested as potential therapeutic targets. Among these receptors, the G protein-coupled bile acid receptor 1 (GPBAR1), which is also known as TGR5, has received much attention in preclinical studies.1−4 TGR5 and its bile acid ligands have been suggested to be drivers of the metabolic improvements seen after Roux-en-Y gastric bypass (RYGB) surgery.5,6 As discussed in this Review, bile acid-induced TGR5 activation increases GLP-1 and insulin release, stimulates resting thermogenesis, and decreases inflammation, which are effects that could be beneficial in the treatment of obesity and type 2 diabetes.1,2
TGR5 was the first transmembrane G protein-coupled receptor shown to be
responsive to bile acids.7,8 It predominantly transmits its signal by increasing
intracellular concentrations of cyclic AMP (cAMP), leading to rapid phosphorylation of downstream kinases. TGR5 is expressed in various cell types
involved in bile acid secretion, the anti-inflammatory response, and energy
metabolism, including gallbladder epithelial cells (cholangiocytes), gallbladder
smooth muscle cells, Kupffer cells, intestinal L cells, pancreatic β cells, skeletal 8 muscle cells, nerve cells, and brown adipocytes8−10 (panel 1). Considering the meal-dependent rhythm of bile acid secretion—and thereby exposure of TGR5
to its ligand—in metabolically active tissues, this receptor might be regarded as a nutrient sensor, ideally placed to regulate integration of postprandial metabolic processes involved in trafficking, storage, and oxidation of nutrients.19 However, the interplay of nutrients, different bile acids and their conjugates, GLP-1, insulin, and gastrointestinal transit time is complex and highly variable. TGR5 expression and function have mainly been studied in rodents and in vitro, and clinical studies are scarce. Nevertheless, treatments targeting Tgr5 might be promising for the treatment of several conditions such as type 2 diabetes, obesity, and non-alcoholic steatohepatitis.20 To establish the clinical and translational impact of current findings, distinct differentiation between human and animal bile acid physiology and TGR5 function is necessary.
Review: clinical relevance of TGR5
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