Mus musculus
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ABSTRACT:
PROVIDER: PRJNA301896 | ENA |
REPOSITORIES: ENA
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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
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.
2015-11-12 | GSE74913 | GEO
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
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: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:Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that feeding unexpectedly activates intestinal lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the late fed-state gut hormone, fibroblast growth factor-15/19 (FGF15/19). Postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses in mouse intestine revealed that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB), upregulating autophagy/lipolysis network genes after feeding. In HT29 intestinal cells, FGF19 treatment activated lipophagy in a manner dependent on both SHP and TFEB, reducing TG and ApoB48 levels. Mechanistically, feeding-induced FGF15/19 signaling increases nuclear localization of TFEB and SHP via PKCβ/ζ-mediated phosphorylation, leading to transcriptional induction of Ulk1 and Atgl. Collectively, these results demonstrate that after feeding, FGF15/19-activated SHP and TFEB paradoxically activate gut lipophagy, limiting postprandial TG levels. As excess lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.
2022-04-22 | GSE197549 | GEO
Project description:Goal of this study is to identify annotated and non-annotated genes transcriptionally regulated by small heterodime partner (SHP, Nrob2) expression. Liver 5' capped RNA samples from three SHP -/- and three wild type mice were sequenced with Illumina GAII sequencer.
2013-10-22 | E-GEOD-43893 | biostudies-arrayexpress
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
Project description:SHP (small heterodimer partner; NR0B2) belongs to the nuclear hormone receptor superfamily, which regulates numerous developmental and metabolic cellular functions. To study physiological function of SHP, we generated congenic SHP-/- mice on C57Bl/6 background. When the congenic SHP-/- mice were challenged with a western diet (harlan, TD.88137) for 22 weeks, they were resistant to diet induced obesity and hepatic steatosis compared to WT controls. However, their hepatic insulin sensitivity was compromised when assessed with phospho-Akt levels after insulin injection. Therefore, we investigated hepatic gene expression using illumina beadchip array to explore mechanisms underneath the unique liver physiology in SHP-/- mice. Livers were collected from C57Bl/6 wild type and C57Bl/6 SHP-/- mice fed chow or western diet. The 1 microgram of total RNA obtained from individual mouse (n=4 per group) and subjected to illumina beadchip gene expression profiling.
2012-05-16 | E-GEOD-38013 | biostudies-arrayexpress
Project description:SHP (small heterodimer partner; NR0B2) belongs to the nuclear hormone receptor superfamily, which regulates numerous developmental and metabolic cellular functions. To study physiological function of SHP, we generated congenic SHP-/- mice on C57Bl/6 background. When the congenic SHP-/- mice were challenged with a western diet (harlan, TD.88137) for 22 weeks, they were resistant to diet induced obesity and hepatic steatosis compared to WT controls. However, their hepatic insulin sensitivity was compromised when assessed with phospho-Akt levels after insulin injection. Therefore, we investigated hepatic gene expression using illumina beadchip array to explore mechanisms underneath the unique liver physiology in SHP-/- mice.
2012-05-17 | GSE38013 | GEO