1. BILEACIDACTIVATEDRECEPTORS: TALE OF A MULTITASKING FAMILY
Nuclear receptors (NRs) are a largefamily of ligand-activated transcription factors
(Human NR superfamily include48 members) which controlnumerousmetabolic
pathways and processes in various organs, ranging from proliferation to apoptosis,
differentiation and energy homeostasis. Nuclear receptorsas valuable potential
targets for the development of therapeutic agents against a number of pathological
conditionsand diseases. Bile acids, arethe end-productsof cholestrolmetabolism
synthesized in the liver and secreted in the gastrointestinaltract where they
undergoesa transformation bythe 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 receptorscollectively known as Bile acid
activated receptors (BARs). This familyincludes NR such as The farnesoid X receptor
(FXR), theVitamin D receptor (VDR), thepregnane-x-receptor (PXR) among others
and G-protein coupled receptorssuch as GPBAR1 (TGR5). FXR isa bile sensor that
acts in coordination with other nuclear receptors to regulateessential steps in bile
acid uptake, metabolism and excretion. FXR shares the generalarchitecture of other
NR receptorsacting as an heterodimer with RXR (retinoid-x-receptor). In addition,
FXR is involved in lipid and glucose homeostasis. FXR ligands endowed with
agonistic activity areunder development for the treatment of metabolic disorders
linked to insulin resistance. GPBAR1 is a receptor regulating energy expenditureand
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
-Potentialclinical application