Analysis of tumor-bearing Farnesoid X Receptor and Small heterodimer Partner double knockout and control WT mice in both sexes
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PROVIDER: PRJNA636202 | ENA |
REPOSITORIES: ENA
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Project description:The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. Therefore, we investigated the myocardial gene expression in a SHP deletion animal model.
2017-12-01 | E-MTAB-5329 | biostudies-arrayexpress
Project description:Mice were aged to a year and their livers were collected and analyzed at the end of the experiment. All the mice used in this study are on C57/B6 background.
2020-06-15 | GSE151524 | GEO
Project description:Comparison of gene expression in adult male mouse livers between wildtype mice and Transgenic mice expressing human Small Heterodimer Partner in hepatocytes.
2006-01-01 | E-MEXP-294 | biostudies-arrayexpress
Project description:Small Heterodimer Partner (SHP/NR0B2) is an unusual orphan nuclear receptor that does not have a DNA binding domain and acts as a co-repressor for many transcriptional factors, including LRH-1, SREBPs, FOXA1, and AhR, which inhibits expression of its target genes. To explore global intestinal functions of SHP, WT and SHP-KO mice were fed for 6 h after fasting overnight. In SHP-KO mice, 1,707 genes were upregulated, and 1,055 genes downregulated by 2-fold or more compared to WT mice. In GO analysis, intestinal genes upregulated with the highest significance were involved in the transport of ions, lipids, and hormones, and in cholesterol metabolic processes; whereas genes downregulated were involved in the cell cycle, the immune response, and apoptosis. Remarkably, expression of genes important for cholesterol absorption, including Npc1l1, sterol biosynthetic genes, including Hmgcr, and key intestinal bile acid transporters, Asbt and Ost-alpha/beta, was altered in SHP-KO mice compared to WT mice. Overall, in this study, SHP was shown to be a gene-specific transcriptional partner of SREBP-2 to epigenetically inhibit cholesterol-regulating genes, including Npc1l1, in the late-fed state.
2019-02-23 | GSE126939 | GEO
Project description:Small Heterodimer Partner and Fibroblast Growth Factor-19 Inhibit Intestinal Npc1l1 Expression and Cholesterol Absorption
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Project description:Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR(-/-) and SHP(-/-) mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR(-/-) mice and therefore, increased SHP expression in FXR(-/-) mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR(-/-) mice with overexpression of SHP in hepatocytes (FXR(-/-)/SHP(Tg)) and determined the contribution of SHP in HCC development in FXR(-/-) mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR(-/-) mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR(-/-) mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver.
| S-EPMC4039201 | biostudies-literature
Project description:As a unique nuclear receptor with only ligand-binding but no DNA-binding domain, small heterodimer partner (SHP) interacts with many transcription factors to inhibit their function. However, the regulation of SHP expression is not well understood. SHP is highly expressed in the liver, and previous studies have shown farnesoid X receptor (FXR) highly induces SHP by binding to a FXR response element (FXRRE) in the promoter of the Nr0b2 gene, which encodes SHP. The FXR-SHP pathway is critical in maintaining bile acid and fatty acid homeostasis. After genome-wide FXR binding by chromatin immunoprecipitation (ChIP) coupled to massively parallel sequencing (ChIP-seq), a novel FXRRE was found in the 3'-enhancer region of the Nr0b2 gene. This downstream inverted repeat separated by one nucleotide is highly conserved throughout mammalian species. We hypothesized that this downstream FXRRE is functional and may mediate a head-to-tail chromatin looping by interacting with the proximal promoter FRXRE to increase SHP transcription efficiency. In the current study, a ChIP-quantitative PCR assay revealed FXR strongly bound to this downstream FXRRE in mouse livers. The downstream FXRRE is important for FXR-mediated transcriptional activation revealed by luciferase gene transcription activation, as well as by deletion and site-directed mutagenesis. The chromatin conformation capture assay was used to detect chromatin looping, and the result confirmed the two FXRREs located in the Nr0b2 promoter and downstream enhancer interacted to form a head-to-tail chromatin loop. To date, the head-to-tail chromatin looping has not been reported in the liver. In conclusion, our results suggest a mechanism by which activation of FXR efficiently induces SHP transcription is through head-to-tail chromatin looping.
| S-EPMC2903909 | biostudies-literature
Project description:Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild-type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow-derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor ? but higher interleukin-10 expressions following toll-like receptor stimulation. FXR-targeted gene small heterodimer partner (SHP) was critical for the regulation of KC response by GW4064. In vivo, the depletion of KCs but not cluster of differentiation (CD) 11b+ cells or knockdown of SHP diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up-regulating SHP in KCs to inhibit the liver proinflammatory response.
| S-EPMC7109340 | biostudies-literature
Project description:Farnesoid X receptor (FXR) functions as a regulator of bile acid and lipid homeostasis and is recognized as a promising therapeutic target for metabolic diseases. The biologic function of FXR is mediated in part by a small heterodimer partner (SHP); ligand-activated FXR enhances SHP expression, and SHP in turn represses the activity of multiple transcription factors. This study aimed to investigate the effect of FXR activation on expression of the major drug-metabolizing enzyme CYP3A4. The effects of 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), a synthetic agonist of FXR, on the expression and activity of CYP3A4 were examined in primary human hepatocytes by using quantitative real-time polymerase chain reaction and S9 phenotyping. In human hepatocytes, treatment of GW4064 (1 μM) for 48 hours resulted in a 75% decrease in CYP3A4 mRNA expression and a 25% decrease in CYP3A4 activity, accompanied by ∼3-fold increase in SHP mRNA expression. In HepG2 cells, SHP repressed transactivation of CYP3A4 promoter by pregnane X receptor (PXR), constitutive androstane receptor (CAR), and glucocorticoid receptor. Interestingly, GW4064 did not repress expression of CYP2B6, another target gene of PXR and CAR; GW4064 enhanced CYP2B6 promoter activity. In conclusion, GW4064 represses CYP3A4 expression in human hepatocytes, potentially through upregulation of SHP expression and subsequent repression of CYP3A4 promoter activity. Clinically significant drug-drug interaction involving FXR agonists and CYP3A4 substrates may occur.
| S-EPMC4407707 | biostudies-literature
Project description:Sirtuin 1 (SIRT1) is a NAD-dependent deacetylase that is critically involved in diverse cellular processes including metabolic disease, cancer, and possibly aging. Despite extensive studies on SIRT1 function, how SIRT1 levels are regulated remains relatively unknown. Here, we report that the nuclear bile acid receptor farnesoid X receptor (FXR) inhibits microRNA-34a (miR-34a) in the liver, which results in a positive regulation of SIRT1 levels. Activation of FXR by the synthetic agonist GW4064 decreases hepatic miR-34a levels in normal mice, and consistently, hepatic miR-34a levels are elevated in FXR-null mice. FXR induces expression of small heterodimer partner (SHP), an orphan nuclear receptor and transcriptional corepressor, which in turn results in repression of p53, a key activator of the miR-34a gene, by inhibiting p53 occupancy at the promoter. MiR-34a decreased SIRT1 levels by binding to the 3'-untranslated region of SIRT1 mRNA, and adenovirus-mediated overexpression of miR-34a substantially decreased SIRT1 protein levels in mouse liver. Remarkably, miR-34a levels were elevated, and SIRT1 protein levels were reduced in diet-induced obese mice, and FXR activation in these mice reversed the miR-34a and SIRT1 levels, indicating an intriguing link among FXR activation, decreased miR-34a, and subsequently, increased SIRT1 levels. Our study demonstrates an unexpected role of the FXR/SHP pathway in controlling SIRT1 levels via miR-34a inhibition and that elevated miR-34a levels in obese mice contribute to decreased SIRT1 levels. Manipulation of this regulatory network may be useful for treating diseases of aging, such as metabolic disease and cancer.
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