Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5) (FXR and TGR5)

The host bile acid receptors, Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5), are critical sensors that coordinate metabolic and inflammatory responses to bile acids [NIH, 2018; MDPI, 2021]. FXR is a nuclear receptor (NR1H4) that functions as a ligand-activated transcription factor, primarily regulating bile acid synthesis, transport, and lipid metabolism in the liver and intestine [Frontiers in Pharmacology, 2020; NIH, 2015]. TGR5 (GPBAR1) is a cell-surface G protein-coupled receptor that mediates rapid signaling pathways, such as cAMP production, to stimulate the secretion of glucagon-like peptide-1 (GLP-1) and enhance energy expenditure [Nature Medicine, 2015; NIH, 2018]. Together, these receptors play a pivotal role in maintaining glucose and lipid homeostasis, and their dysregulation is closely linked to metabolic disorders like non-alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity [Physiology.org, 2019; MDPI, 2024]. Pharmacological modulation of both FXR and TGR5 has emerged as a promising therapeutic strategy, with dual agonists like INT-767 aiming to combine the potent metabolic benefits of FXR activation with the insulin-sensitizing and anti-inflammatory effects of TGR5 [Hepatology, 2018; NIH, 2015]. However, therapeutic development faces significant challenges, including drug-induced pruritus and unfavorable alterations in cholesterol profiles, which are common side effects associated with potent bile acid receptor activation [Journal of Hepatology, 2019; ResearchGate, 2024].

Other names

NR1H4GPBAR1Bile acid receptorTakeda G protein-coupled receptor 5M-BARGPR131BARHRR-1RIP14

FXR acts as a nuclear transcription factor that, upon bile acid binding, heterodimerizes with the retinoid X receptor (RXR) to regulate the expression of genes involved in bile acid synthesis (e.g., inhibiting CYP7A1 via SHP or FGF15/19) and transport (e.g., BSEP) [NIH, 2015; Frontiers in Pharmacology, 2020]. TGR5 is a membrane-bound G protein-coupled receptor that, when activated by bile acids, triggers the Gs-cAMP-PKA signaling pathway, leading to the secretion of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells and promoting energy expenditure in brown adipose tissue and muscle [Nature Medicine, 2015; NIH, 2018]. Dual modulation of these receptors provides a synergistic approach to improving metabolic homeostasis and reducing inflammation [Hepatology, 2018].