BILE ACID ACTIVATED RECEPTORS: TALE OF A MULTITASKING FAMILY

Nuclear receptors (NRs) are a large family of ligand-activated transcription factors (Human NR superfamily include 48 members) which control numerous metabolic pathways and processes in various organs, ranging from proliferation to apoptosis, differentiation and energy homeostasis. Nuclear receptors as valuable potential targets for the development of therapeutic agents against a number of pathological conditions and diseases. Bile acids, are the end-products of cholestrol metabolism synthesized in the liver and secreted in the gastrointestinal tract where they undergoes a transformation by the intestinal microbiota. In addition to their role in regulating lipid and cholesterol absorption in the small intestinal, bile acids area signaling molecules acting on wide range of receptors collectively known as Bile acid activated receptors (BARs). This family includes NR such as The farnesoid X receptor (FXR), the Vitamin D receptor (VDR), the pregnane-x-receptor (PXR) among others and G-protein coupled receptors such as GPBAR1 (TGR5). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps in bile acid uptake, metabolism and excretion. FXR shares the general architecture of other NR receptors acting as an heterodimer with RXR (retinoid-x-receptor). In addition, FXR is involved in lipid and glucose homeostasis. FXR ligands endowed with agonistic activity are under development for the treatment of metabolic disorders linked to insulin resistance. GPBAR1 is a receptor regulating energy expenditure and has relevance in the treatment of insulin resistance and diabetes along with inflammation and immune dysfunction.

Objectives

- To describe cholesterol/bile acid metabolism and receptors

- Biology of BAR

- Medicinal chemistry of FXR and GPBAR1

-Potential clinical application