Quantifying forms and functions of intestinal bile acid pools in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE256113 | GEO | 2024/02/21
REPOSITORIES: GEO
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Project description:Bile acids (BAs) are a fundamental class of lipid emulsifying metabolites that are synthesized by hepatocytes, important for fat-soluble vitamin absorption, and maintained in vivo through enterohepatic circulation between the liver and ileum1. However, BAs are also lipophilic detergents and can be cytotoxic in enterohepatic tissues2. Whereas several nuclear receptors are known to prevent BA-driven toxicity in hepatocytes and intestinal enterocytes3, the mechanisms by which mucosal immune cells protect themselves from BAs in the ileum remains poorly understood. We recently reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to protect against BA toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here, we identify the BA- and xenobiotic-sensing nuclear receptor, constitutive androstane receptor (CAR/NR1I3), as a key regulator of MDR1 expression in mucosal Teff cells. CAR promotes large-scale transcriptional reprogramming of Teff cells in the small intestine lamina propria (siLP), which shares similarities with CAR-dependent gene expression in hepatocytes and involves the induction of both detoxifying enzymes and transporters, as well as anti-inflammatory cytokines, such as Il10. Accordingly, loss of CAR in Teff cells exacerbates, whereas pharmacologic CAR activation suppresses, BA-driven ileitis in T cell-reconstituted Rag1-/- mice. Further, CAR transcriptional activity is evident in human CD4+ T cells, but only in 4+7+CCR9+ Teff cells that are licensed for small bowel homing. In these cells, CAR activation also promotes cyto-protective and anti-inflammatory gene expression, including a core set of transcriptional targets that are similarly regulated by CAR in mouse mucosal Teff cells and hepatocytes. Together, these results suggest that mucosal T cells rely on CAR to activate a hepatocyte-like transcriptional response in the ileum that detoxifies BAs and safeguards immune homeostasis. Pharmacologic activation of this program may offer an unexpected strategy to treat small bowel Crohn’s disease.
2021-02-13 | GSE149219 | GEO
Project description:Bile acids (BAs) are a fundamental class of lipid emulsifying metabolites that are synthesized by hepatocytes, important for fat-soluble vitamin absorption, and maintained in vivo through enterohepatic circulation between the liver and ileum1. However, BAs are also lipophilic detergents and can be cytotoxic in enterohepatic tissues2. Whereas several nuclear receptors are known to prevent BA-driven toxicity in hepatocytes and intestinal enterocytes3, the mechanisms by which mucosal immune cells protect themselves from BAs in the ileum remains poorly understood. We recently reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to protect against BA toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here, we identify the BA- and xenobiotic-sensing nuclear receptor, constitutive androstane receptor (CAR/NR1I3), as a key regulator of MDR1 expression in mucosal Teff cells. CAR promotes large-scale transcriptional reprogramming of Teff cells in the small intestine lamina propria (siLP), which shares similarities with CAR-dependent gene expression in hepatocytes and involves the induction of both detoxifying enzymes and transporters, as well as anti-inflammatory cytokines, such as Il10. Accordingly, loss of CAR in Teff cells exacerbates, whereas pharmacologic CAR activation suppresses, BA-driven ileitis in T cell-reconstituted Rag1-/- mice. Further, CAR transcriptional activity is evident in human CD4+ T cells, but only in 4+7+CCR9+ Teff cells that are licensed for small bowel homing. In these cells, CAR activation also promotes cyto-protective and anti-inflammatory gene expression, including a core set of transcriptional targets that are similarly regulated by CAR in mouse mucosal Teff cells and hepatocytes. Together, these results suggest that mucosal T cells rely on CAR to activate a hepatocyte-like transcriptional response in the ileum that detoxifies BAs and safeguards immune homeostasis. Pharmacologic activation of this program may offer an unexpected strategy to treat small bowel Crohn’s disease.
2021-02-13 | GSE149218 | GEO
Project description:Background and Aims - Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for human diseases, but differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. Methods - BA-related parameters, hepatic and intestinal gene expression patterns, liver morphology and intestinal barrier function were assessed in male and female Cyp2c70-/- mice and WT controls at different ages. Effects of ursodeoxycholic acid (UDCA) treatment were evaluated in young adult female mice. Results – Cyp2c70-/- mice were completely devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. BA pool size was unaffected in young-adult male but reduced by 40% in female Cyp2c70-/- mice. Interestingly, plasma BAs and transaminases were highest in Cyp2c70-/- mice at weaning and spontaneously decreased with age. Although bile flow and biliary BA secretion were unchanged in young-adult Cyp2c70-/- mice, indicating absence of cholestasis, plasma BA and transaminase levels were still elevated. These young-adult Cyp2c70-/- mice displayed cholangiocyte proliferation, mild portal fibrosis, altered microbiome composition and increased gut permeability. Only the female Cyp2c70-/- mice developed bridging fibrosis with age (7-8 months). UDCA treatment normalized hepatic and intestinal functions and fully restored liver morphology in female Cyp2c70-/- mice. Conclusion – Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features which progress to bridging fibrosis in female mice only. These consequences of Cyp2c70-deficiency are fully restored by treatment with UDCA.
2020-12-22 | GSE138779 | GEO
Project description:Farnesoid X receptor (FXR) is a ligand activated nuclear receptor belonging to the nuclear receptor superfamily. Bile acids (BAs) are the endogenous ligand for FXR. FXR is a master regulator of BA homestasis, including BA synthesis, metabolism, transport, and enterohepatic circulation of BAs. Besides, FXR is involved in regulating diverse physioligical function in both humans and mice. GW4064 is a synthetic FXR agonist which selectively activates FXR and induce the transcription of FXR target genes.
2014-07-24 | GSE57305 | GEO
Project description:Background and Aims: Although the zinc finger transcription factor GATA4 has been implicated in regulating jejunal gene expression, the contribution of GATA4 in controlling jejunal physiology has not been addressed. Methods: We generated mice in which the Gata4 gene was specifically deleted in the small intestinal epithelium. Measurements of plasma cholesterol and phospholipids, intestinal absorption of dietary fat and cholesterol, and gene expression were performed on these animals. Results: Mice lacking GATA4 in the intestine displayed a dramatic block in their ability to absorb cholesterol and dietary fat. Comparison of the global gene expression profiles of control jejunum, control ileum, and GATA4 null jejunum by gene array analysis demonstrated that GATA4 null jejunum lost expression of 53% of the jejunal-specific gene set and gained expression of 47% of the set of genes unique to the ileum. These alterations in gene expression included a decrease in mRNAs encoding lipid and cholesterol transporters as well as an increase in mRNAs encoding proteins involved in bile acid absorption. Conclusion: Our data demonstrate that GATA4 is essential for jejunal function including fat and cholesterol absorption and confirm that GATA4 plays a pivotal role in determining jejunal versus ileal identity. Experiment Overall Design: Total RNA was harvested from the following sources and used to Affymetrix array analysis following manufacturer defined protocols: Experiment Overall Design: control jejunum (Gata4loxP/+VilCre), 3 male mice, adult (6-8 wk) Experiment Overall Design: mutant jejunum (Gata4loxP/-VilCre), 3 male mice, adult (6-8 wk) Experiment Overall Design: control ileum (Gata4loxP/+VilCre), 3 male mice, adult (6-8 wk). Experiment Overall Design: A total of nine Mouse Genome 430_2.0 arrays were hybridized for this study. Experiment Overall Design: Jejunum was defined as 10 cm from the pyloric sphincter, and ileum was defined as 1 cm from the cecum. The animals used to harvest control jejunum and ileum were independent of each other.
2008-10-25 | E-GEOD-11194 | biostudies-arrayexpress
Project description:Bile acids act as ligands for several nuclear receptors expressed in the small intestine, especially the terminal ileum. Bile acid pool composition can be influenced by health and disease states. Here, we used RNA-seq to investigate the effects of altering bile acid pool composition on gene expression in ileal organoids.
2020-07-19 | GSE144398 | GEO
Project description:Orally administered drugs are absorbed and metabolized in the intestine. In order to accurately predict pharmacokinetics in the intestine, it is essential to understand the intestinal expression profiles of genes related to drug absorption, distribution, metabolism, and excretion (ADME). However, in many previous studies, gene expression analysis in the intestine has been carried out using specimens from cancer patients. In this study, in order to obtain a more accurate gene expression profile, biopsy samples were collected from 14 patients under endoscopic observation and RNA-seq analysis was performed. Gene expression analysis of drug metabolizing enzymes (CYPs), non-CYP enzymes, nuclear receptors, drug conjugating enzymes (UGTs and SULTs), and apical and basolateral drug transporters was performed in biopsy samples from the duodenum, ileum, colon, and rectum. The proportions of the CYPs expressed in the ileum were 25% (CYP3A4), 19% (CYP2C18), and 14% (CYP3A5). CYP3A4 and CYP2C19 were highly expressed in the duodenum and ileum, but not in the colon and rectum. In the ileum, apical transporters such as P-gp, PEPT1, BCRP, MRP2, and ASBT were strongly expressed, and the expression levels of P-gp and ASBT in the ileum were higher than those in other regions. In the ileum, basolateral transporters such as OSTα, OSTβ, and MRP3 were strongly expressed. Furthermore, we identified specific markers for the duodenum, ileum, colon, and rectum by conducting comprehensive gene expression analysis. We succeeded in obtaining gene expression profiles of drug ADME-related genes in vivo human intestinal epithelial cells. We expect that this information would be useful for accurate prediction of the pharmacokinetics of oral drugs.
2021-04-30 | GSE156453 | GEO
Project description:Background: Despite recent studies investigating the involvement of single cells in regional differences of the small intestine (SI), the metabolic contribution of the duodenum, jejunum, and ileum to the overall intestinal metabolism is still unclear. Basic procedures and main findings: Using an untargeted proteomics approach, we identified similarities and differences between the three intestinal tracts of C57BL/6J mice and found that proteins highly abundant in the mouse ileum correlated with high ileal expression of the corresponding genes in humans. Consistent with human data, we detected increasing abundance of lysosomal acid lipase (LAL) in C57BL/6J mice from the duodenum to ileum. LAL is the only enzyme known to degrade triacylglycerols and cholesteryl esters within the lysosome. Lipid accumulation in various organs along with gastrointestinal disturbances and malabsorption are typical features of patients and mice with LAL deficiency. We previously demonstrated that macrophages massively infiltrate the SI of Lal-deficient (KO) mice, especially the duodenum. To identify potential mechanisms behind the intestinal lipid accumulation and infiltration of immune cells, we used untargeted proteomics. Our results revealed a general inflammatory response and a common lipid-associated macrophage phenotype in all three intestinal segments of Lal KO mice, accompanied by higher expression of GPNMB and increased concentrations of circulating sTREM2. However, only duodenal macrophages activated a metabolic switch from lipids to other pathways such as glycolysis, TCA cycle, and oxidative phosphorylation to meet their high energy demand. Unexpectedly, these pathways were downregulated in the jejunum and ileum of Lal KO mice. Conclusion: Our results provide new insights into the process of absorption in control mice and the basis for novel markers of LAL-D and/or systemic inflammation in LAL-D.
2024-02-20 | PXD048378 | Pride
Project description:Background and Aims: Although the zinc finger transcription factor GATA4 has been implicated in regulating jejunal gene expression, the contribution of GATA4 in controlling jejunal physiology has not been addressed. Methods: We generated mice in which the Gata4 gene was specifically deleted in the small intestinal epithelium. Measurements of plasma cholesterol and phospholipids, intestinal absorption of dietary fat and cholesterol, and gene expression were performed on these animals. Results: Mice lacking GATA4 in the intestine displayed a dramatic block in their ability to absorb cholesterol and dietary fat. Comparison of the global gene expression profiles of control jejunum, control ileum, and GATA4 null jejunum by gene array analysis demonstrated that GATA4 null jejunum lost expression of 53% of the jejunal-specific gene set and gained expression of 47% of the set of genes unique to the ileum. These alterations in gene expression included a decrease in mRNAs encoding lipid and cholesterol transporters as well as an increase in mRNAs encoding proteins involved in bile acid absorption. Conclusion: Our data demonstrate that GATA4 is essential for jejunal function including fat and cholesterol absorption and confirm that GATA4 plays a pivotal role in determining jejunal versus ileal identity. Keywords: genetic modification
2008-09-01 | GSE11194 | GEO
Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.
2023-08-19 | GSE240733 | GEO