The role of hepatic XBP1 in FXR null mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA833429 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18972855.fastq.gz | Fastqsanger.gz | |||
| SRR18972856.fastq.gz | Fastqsanger.gz | |||
| SRR18972857.fastq.gz | Fastqsanger.gz | |||
| SRR18972858.fastq.gz | Fastqsanger.gz | |||
| SRR18972859.fastq.gz | Fastqsanger.gz |
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Project description:X-box binding protein 1 (XBP1) is a key component of the unfolded protein response that is activated in response to ER stress. Farnesoid X receptor (FXR) null (Fxr-/-) mice have elevated bile acid levels and progressive liver injury. Hepatic XBP1 pathway is activated in older Fxr-/- mice. This project is to investigate the role of liver XBP1 in Fxr-/- mice.
2022-09-19 | GSE201902 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation.
2010-12-10 | GSE20599 | GEO
Project description:Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. We show that FXR isoforms have specific effects on hepatic metabolism and uncover novel pathways under their control. Gene expression profiling of hepatocytes expressing each FXR variant revealed large differences in their target gene sets. Notably, FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves insulin sensitivity. FXRα2 expression in Fxr-/- mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression. Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Thus, pharmacological or lifestyle interventions, such as exercise, aimed at modulating hepatic FXR splicing may improve the therapeutic efficacy of FXR agonists.
2015-09-28 | GSE73035 | GEO
Project description:Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and -defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated Acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. FXR-WT or the FXR-K217Q mutant was expressed in lean mice and FXR-WT or the FXR-K217R mutant was expressed in obese mice by adenoviral infection. One week after infection, mice were treated with GW4064 (30 mg/kg in corn oil) overnight before sacrifice and hepatic expression was analyzed by Illumina microarray.
2014-10-17 | E-GEOD-62414 | biostudies-arrayexpress
Project description:Xbp1 is an important regulator of unfolded protein response and lipid metabolism. Its dyregulation has been associcated in human NASH. Feeding a high fat diet with fructose/sucrose to mice causes progressive, fibrosing steatohepatitis. This study is to use RNA-Seq to identify differentially expressed genes in hepatic Xbp1 deficient mice livers fed with a high fat diet compared to controls. Hepatic Xbp1 deficient mice or flox controls were fed either regular chow or a high fat diet (n=4). Samples from each cohort were pooled into two replicates.
2016-01-07 | E-GEOD-64824 | biostudies-arrayexpress
Project description:Microarray analysis to examine the relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (CPR) null mice. Keywords: ordered
2004-07-11 | GSE1468 | GEO
Project description:Cirrhosis is a late stage of fibrosis impairing liver function. Genetic animal models for cirrhosis are lacking, and molecular mechanisms remain unknown. We report the first murine genetic model recapitulating human cirrhosis induced by hepatocyte-specific elimination of MCRS1, a member of NSL and INO80 chromatin-modifier complexes. MCRS1 loss in hepatocytes modulates the expression of bile acid (BA) transporters, with a pronounced NTCP downregulation, concentrating BAs in liver sinusoids, thereby activating hepatic stellate cell (HSC) via FXR. Consistently, genetic FXR ablation in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts HDAC1 from its H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays loss of nuclear MCRS1 and decreased NTCP expression. Thus, histone acetylation-mediated dysregulation of BA transporters, and consequently FXR activation by BAs in HSCs represent a central and universal signaling event in cirrhosis. The data is from single-nuclei RNA-seq of whole-liver collected during autopsy of 4 individuals with COVID-19 and PMI < 4.5 hours
2023-07-03 | GSE179548 | GEO
Project description:Xbp1 is an important regulator of unfolded protein response and lipid metabolism. Its dyregulation has been associcated in human NASH. Feeding a high fat diet with fructose/sucrose to mice causes progressive, fibrosing steatohepatitis. This study is to use RNA-Seq to identify differentially expressed genes in hepatic Xbp1 deficient mice livers fed with a high fat diet compared to controls.
2016-01-07 | GSE64824 | GEO
Project description:BACKGROUND AND AIM: We previously established that endoplasmic reticulum stress leads to unfolded protein response (UPR) that promotes liver fibrosis by activating hepatic stellate cell (HSC). We aimed to determine the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways, in the fibrogenic HSC activation. METHODS: XBP1 expression was measured by qPCR in tunicamycin-treated human HSC lines (TWNT4 and LX2) and culture-activated human primary HSCs. XBP1 was overexpressed in primary human HSCs and the HSC lines, and fibrogenic genes (COL1A1, ACTA2, PDGFRB, MMP2, TIMP1) and encoded proteins were assessed by qPCR and Western blotting, respectively. Autophagy was inhibited by knockdown of ATG7. Genome-wide transcriptome profiling was performed to determine modulated molecular pathway by XBP1. In vivo XBP1 activation was assessed in transcriptome datasets of fibrotic mouse models and immunohistochemistry of human liver tissues. RESULTS: XBP1 overexpression accompanied both tunicamycin- and culture-based HSC activation. Ectopic overexpression of XBP1 induced fibrogenic gene expression in the HSC lines, which was inhibited by knockdown of ATG7. UPR pathway together with PDGFRB pathway, a hallmark of HSC activation, were induced in transcriptome profiles of XBP1-transduced HSC lines. Some known fibrogenic pathways such as transforming growth factor (TGF)-beta pathway were not induced, suggesting partial contribution of XBP1 to the entire fibrogenic HSC activation machinery. XBP1 target gene signature defined in our XBP1-overexpressing HSC lines was significantly induced in liver tissue transcriptome profiles of carbon tetrachloride-treated or bile duct-ligated mouse models, and XBP1 and alpha-smooth muscle actin (encoded by ACTA2, another hallmark of HSC activation) were co-localized in human fibrotic liver tissues, collectively supporting involvement of XBP1 in HSC activation and fibrogesis in vivo. CONCLUSIONS: XBP1-mediated UPR is at least partially responsible for fibrogenic HSC activation via autophagy.
2016-12-21 | GSE78070 | GEO