SMRT regulation of nuclear receptors orchestrates bile acid homeostasis

Abstract

Nuclear receptors are key effectors of metabolic programs; however, the contribution of co-regulatory complexes in maintaining metabolic homeostasis is not fully understood. Here, we show that modulation of the constitutive androstane receptor (CAR) by the co-repressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is required for bile acid (BA) homeostasis. Transcriptional changes in the livers of mice harboring a targeted disruption in one of the nuclear receptor-interacting domains (RIDs), SMRTmRID1 mice, revealed increased expression of CAR target genes involved in BA export. Consistent with this, SMRTmRID1 mice challenged with a high-fat diet showed increased BAs in serum and urine with commensurate decreases in the liver and intestines. Notably, the reduction in intestinal BAs led to decreased activity of the BA receptor farnesoid X receptor (FXR). This reduction in FXR activity compromised the integrity of the intestinal barrier, increased bacterial burden, and augmented intestinal inflammation. Moreover, SMRTmRID1 mice were susceptible to intestinal damage, with higher mortality rates in acute colitis and colitis-associated cancer models. Treatment with a synthetic FXR agonist (XL335) rescued SMRTmRID1 mice during acute colitis. Collectively, these studies highlight the importance of SMRT in maintaining BA homeostasis through direct and indirect regulation of hepatic CAR and intestinal FXR activity, respectively, and point to potential therapeutic routes for combating intestinal pathologies associated with a high-fat diet. Nuclear receptors (NRs) have a crucial role in gene transcription regulation, impacting metabolic homeostasis. This study explores the disruption of the silencing mediator for retinoid and thyroid hormone receptors (SMRT) network in high-fat diet (HFD)-fed SMRTmRID1 mice, revealing its impact on bile acid (BA) homeostasis and intestinal health. Researchers used SMRTmRID1 knock-in mice, which have mutations in the RID1 domain, to study the effects of impaired SMRT–NR interactions. They found that disrupted SMRT function derepresses hepatic constitutive androstane receptor activity, leading to altered BA metabolism and reduced intestinal BA levels. This reduction impairs farnesoid X receptor-mediated mucosal defense, increasing intestinal permeability and inflammation. The study highlights the importance of the SMRT–NR network in maintaining BA homeostasis and suggests that farnesoid X receptor activation could mitigate intestinal dysfunction. Future research could explore tissue-specific SMRT models to further understand these interactions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.