Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding

Abstract

Edited by Dennis R. VoelkerNuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and nonalcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor ␣ (RXR␣) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXR␣. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/ RXR␣ heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.

Can You Trust Your Gut? Implicating a Disrupted Intestinal Microbiome in the Progression of NAFLD/NASH

“…Like most NRs, FXR has a N terminal ligandindependent activation function (AF1), a highly conserved DNA-binding domain (DBD), a ligand binding domain (LBD), and finally a C-terminal ligand-dependent activation function (AF2) (51). FXR forms a heterodimer with retinoid X-receptor (RXR), and when there is no ligand binding, the FXR-RXR heterodimer remains bound to FXR responsive elements (FXREs) within the promoters of FXR target genes, bound to co-repressors (52). Upon ligand-induced activation, corepressors leave the FXR-RXR heterodimer to make way for co-activators, thus upregulating target gene transcription (52).…”

“…FXR forms a heterodimer with retinoid X-receptor (RXR), and when there is no ligand binding, the FXR-RXR heterodimer remains bound to FXR responsive elements (FXREs) within the promoters of FXR target genes, bound to co-repressors (52). Upon ligand-induced activation, corepressors leave the FXR-RXR heterodimer to make way for co-activators, thus upregulating target gene transcription (52). While FXR was initially found to be weakly activated by farnesoid, an intermediate of mevalonate metabolism, it was later found that despite low affinity, BAs potently activate FXR in the order of CDCA > LCA = DCA > CA (53).…”

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

“…An emerging therapeutic target for NAFLD is the farnesoid X receptor (FXR, encoded by NR1H4 ), a transcription factor that regulates lipid and glucose metabolism and hepatic inflammation. FXR activation induces the expression of genes involved in lipoprotein metabolism/clearance and represses the activity of genes involved in triglyceride synthesis . The main mechanism mediating these effects is inhibition of lipogenesis and induction of beta‐oxidation .…”

“…FXR activation induces the expression of genes involved in lipoprotein metabolism/clearance and represses the activity of genes involved in triglyceride synthesis. 8,9 The main mechanism mediating these effects is inhibition of lipogenesis 10,11 and induction of beta-oxidation. 12 However, the regulatory effects of FXR on 1-deoxysphingolipid metabolism have never been studied.…”

FXR expression in a rat model of hilar cholangiocarcinoma

“…Farnesyl X receptor (FXR) is related with bile acid metabolism, which is important in bile acid secretion. In former experiment we have detected that bile salt export pump (Bsep), a target gene of FXR,expression decreased in hilar cholangiocarcinoma tissues of rats, which led us to investigate the role of FXR, whether the role of FXR is enhanced or diminished in hilar cholangiocarcinoma [1][2][3].…”