FXR crosstalk with other nuclear receptors.

Abstract

The farnesoid X receptor (FXR), a nuclear receptor (NR), plays a key role in balancing bile acid (BA), lipid, and glucose metabolism. By partnering with the retinoid X receptor (RXR), FXR influences gene transcription critical to these metabolic pathways. It also interacts with other NRs, including the pregnane X receptor (PXR), liver X receptor (LXR), and vitamin D receptor (VDR), creating an intricate signalling network. FXR activation triggers the production of small heterodimer partner (SHP), which suppresses cholesterol 7 alpha-hydroxylase (CYP7A1), the enzyme controlling BA synthesis. It also regulates lipid metabolism by controlling sterol regulatory element-binding protein 1c (SREBP-1c) and affects glucose balance. LXR, activated by oxysterols, supports reverse cholesterol transport (RCT) by regulating the expression of adenosine triphosphate binding cassette A1 (ABCA1) and adenosine-binding cassette sub-family G member 1 (ABCG1). Since FXR affects LXR-regulated genes, it indirectly modulates cholesterol homeostasis. Meanwhile, PXR, a xenobiotic sensor responsive to diverse compounds, such as BAs, regulates genes involved in drug detoxification and transport. FXR activation enhances PXR expression, influencing BA metabolism and removal. VDR, which responds to vitamin D and specific BAs such as lithocholic acid, plays a role in calcium balance and xenobiotic processing. The interplay among these NRs underscores FXR's central role in metabolic regulation and its potential as a therapeutic target for metabolic disorders.