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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of small heterodimer partner deficiency (SHP) knockout mice heart

ABSTRACT: The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) Î³ expression. SHP is also abundantly expressed in the myocardium. Therefore, we investigated the myocardial gene expression in a SHP deletion animal model.

ORGANISM(S): Mus musculus

SUBMITTER: Jung Hun Ohn

PROVIDER: E-MTAB-5329 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

Project description:Background: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, Small Heterodimer Partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19. Genome-wide SHP binding profiles in hepatic chromatin in mice under treatment of FGF19 or vehicle were generated using high throughput sequencing followed by chromatin immunoprecipitation.

2015-11-12 | E-GEOD-74913 | biostudies-arrayexpress

Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

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

Intestinal FGF15/19 physiologically represses hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

Project description:Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. Fibroblast Growth Factor-19 (FGF19, mouse FGF15) is a late fed-state gut hormone that decreases hepatic lipid levels by unclear mechanisms. We examined whether FGF15/19 and FGF15/19-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF19, have overlapping CpG islands. FGF19 treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to DNA methylation and gene repression. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. These results demonstrate that FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.

2020-09-23 | GSE158359 | GEO

Small Heterodimer Partner and Fibroblast Growth Factor-19 Inhibit Intestinal Npc1l1 Expression and Cholesterol Absorption

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

Expression data from SHP specific siRNA or nonspecefic siRNA transfected rat astrocytes

Project description:To clarify the effect of SHP in LXRs-mediated signaling pathway, we performed global gene expression analysis of SHP siRNA transfected- or control siRNA transfected- astrocytes after IFN-Î³ and LXRs agonist. Microarray analysis revealed that expression of several genes encoding inflammatory mediators were reversed in SHP siRNA transfected-astrocytes, when compared with control siRNA transfected-astrocytes. Primary astrocytes were cultured from the cerebral cortices of 1 day-old Sprague-Dawley rats. The astrocytes were transfected with control siRNA or SHP siRNA and treated with IFN-Î³ in the presence or absence of GW for 3 h.

2016-01-21 | E-GEOD-76704 | biostudies-arrayexpress

Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

2015-11-12 | GSE74913 | GEO

MicroRNA profiling of mouse wild type and SHP knock-out liver

Project description:The microRNA expression profiles between wild type 2-month old mouse liver and small heterodimer partner (SHP) knockout mouse liver was compared using microRNA array.

2008-09-13 | E-MEXP-1721 | biostudies-arrayexpress

Microarray analysis of genes regulated by SHP in wild-type and ob/ob mice.

Project description:Liver gene expression was compared in wild type, SHP knockout, ob/ob, and ob/ob SHP double mutant mice. A total of eight samples were analyzed using Affymetrix arrays. Each of the four genotypes studied were assayed in duplicate.

2012-09-12 | E-GEOD-40775 | biostudies-arrayexpress

SHP-1(FLAG) AP-MS, with/without TAOK3 and/or SRC kinase

Project description:To understand the influence of phosphorylation on the protein-protein interactions, we performed an AP-MS of SHP-1(FLAG) in HEK293T/17 cells co-transfected with TAOK3 and/or SRC kinase. Whilst TAOK3 phosphorylates Thr-394, SRC phosphorylates Tyr536 and Tyr564.

2024-01-04 | PXD042497 | Pride

Transcription profiling of mouse wild type adult male mouse livers vs transgenic mice expressing human Small Heterodimer Partner in hepatocytes

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

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