Small Heterodimer Partner and Fibroblast Growth Factor-19 Inhibit Intestinal Npc1l1 Expression and Cholesterol Absorption
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA523814 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8609032.fastq.gz | Fastqsanger.gz | |||
| SRR8609033.fastq.gz | Fastqsanger.gz | |||
| SRR8609034.fastq.gz | Fastqsanger.gz | |||
| SRR8609035.fastq.gz | Fastqsanger.gz | |||
| SRR8609036.fastq.gz | Fastqsanger.gz |
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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: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:Background & aimsThe nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption.MethodsWe performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells.ResultsWe found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription factor 2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity.ConclusionsPostprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
| S-EPMC6409196 | biostudies-literature
Project description:Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide. Hypercholesterolemia is a risk factor of atherosclerosis. This study evaluated the effects of three doses of Totum-070 (3.5%, 4.25% and 5% of diet for 12 weeks; HFD-Totum-070 groups), a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia (HFD group). Several functional tests were performed in vivo to characterize the effect of Totum-070 on lipoprotein metabolism. Molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced total cholesterol (-41%), non-HDL cholesterol (-47%) and triglycerides (-46%) in a dose-dependent manner, compared with HFD, without any effects on food intake or body weight. HFD-induced steatosis also was significantly decreased. Gene expression analysis in liver and intestine highlighted Totum-070 effects on metabolic pathways and a strong anti-inflammatory effect. Upon challenge with olive oil gavage, post-prandial lipemia was strongly reduced. Sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group. The dual isotope cholesterol absorption test confirmed the reduction of intestinal cholesterol absorption in Totum-070 supplemented hamsters. These effects were confirmed in Caco2 cells where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, metagenomic analysis of gut microbiota revealed a strong effect of Totum-070 on alpha and beta diversity measures. Compared with the HFD group, the Firmicutes to Bacteroidetes ratio was beneficially reduced in the HFD-hamsters supplemented with Totum-070 groups. Altogether, these findings indicate that Totum-070-mediated inhibition of intestinal cholesterol absorption limits the rise in blood cholesterol in high-fat fed hamsters.
2023-06-30 | GSE227411 | GEO
Project description:The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer to regulate anabolic metabolism. However, the metabolic requirements of PKM2 in tumorigenesis have yielded contradictory results. Herein we discovered that this glycolytic enzyme regulates lipid homeostasis in cancer cell autonomous manner and at systemic levels. Transmembrane protein 33 (TMEM33) was identified as a downstream effector of PKM2, whose expression level positively correlates with plasma total cholesterol level in vivo. Loss of PKM2 leads to up-regulation of TMEM33, which recruits ring finger protein 5 (RNF5) to promote SCAP ubiquitination and degradation, thereby inhibiting Golgi translocation and activation of sterol regulatory element binding protein 1 (SREBP1). Moreover, global PKM2 knockout promoted allografted tumor growth, at least partially attributes to the elevated plasma cholesterol level caused by increased intestinal Niemann-Pick C1-Like 1 (NPC1L1) to facilitate cholesterol absorption. Collectively, PKM2-TMEM33 axis modulates cell autonomous lipid metabolism by regulating SREBP activation. PKM2 in small intestine plays critical functions in controlling systemic cholesterol level. Overall, our results underscore unappreciated functions of PKM2 in lipid homeostasis and imply that combining an allosteric activator of PKM2 with NPC1L1 inhibitor represents a therapeutic invention for cancer treatment.
2021-08-06 | PXD026434 | Pride
Project description:ABSTRACT Background & aims: The role of the intestine in the maintenance of cholesterol homeostasis is increasingly recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport (RCT) pathway, to which both biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway are,however, poorly understood. In the current study we aimed to identify treatment modalities that stimulate TICE and to uncover underlying driving mechanisms. Methods: TICE was assessed in a panel of knock-out and transgenic mice as well as in mice treated with the FXR agonist PX20606 either or not combined with the cholesterol absorption inhibitor ezetimibe. Results: We show that TICE is regulated by intestinal farnesoid X receptor (FXR) via its target fibroblast growth factor 15/19 (FGF15/19) and that the pathway can be stimulated to such an extent that mice excrete ~60% of their total cholesterol content each day. Both PX20606 and FGF19 increased the muricholate/cholate ratio in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool robustly stimulated secretion of cholesterol into the intestinal lumen via the sterol exporting heterodimer ATP binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, we demonstrate that the increase in TICE induced by PX20206 is independent of changes in cholesterol absorption. Conclusions: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Translation of these results to humans may offer new treatment modalities for prevention of cardiovascular disease.
2017-01-10 | GSE74101 | GEO
Project description:Dietary nutrients interact with the gene networks to orchestrate adaptive responses during metabolic stress. Tissue metabolic reprogramming is frequently linked to induction of pathways with pathophysiological consequences. Here we identified Baf60a as a diet-sensitive subunit of the SWI/SNF chromatin-remodeling complexes in the liver that links the consumption of fat- and cholesterol-rich diet to elevated plasma cholesterol levels. The expression of Baf60a in the liver was elevated following western diet feeding. Hepatocyte-specific inactivation of Baf60a reduced bile acid production and intestinal cholesterol absorption, and attenuated diet-induced hypercholesterolemia and atherosclerosis in mice. At the mechanistic level, Baf60a stimulates the expression of hepatic genes involved in bile acid synthesis, modification, and transport through a CAR/Baf60a feedforward regulatory loop. Baf60a is required for the recruitment of the SWI/SNF chromatin-remodeling complexes to facilitate an activating epigenetic switch on the CAR target genes. These studies elucidate an unexpected regulatory pathway that mediates the hyperlipidemic and atherogenic effects of western diet consumption. We used microarrays to elucidate the role of hepatic Baf60a in the regulation of lipid metabolism.
2015-10-03 | GSE73709 | GEO
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:Norwalk virus (NV) is a prototype strain of the noroviruses (family Caliciviridae) which have emerged as major causes of acute gastroenteritis worldwide. We have developed NV replicon systems using reporter proteins such as a neomycin resistant protein (NV replicon-bearing cells) and a green fluorescent protein (pNV-GFP), and demonstrated that these systems were excellent tools to study virus replication in cell culture. In this study, we first performed DNA microarray analysis of the replicon-bearing cells to identify cellular factors associated with NV replication. The analysis demonstrated that genes in lipid (cholesterol) or carbohydrate metabolic pathways were significantly (p< 0.001) changed by the gene ontology analysis. Among genes in the cholesterol pathways, we found that mRNA levels of hydroxymethylglutaryl-CoA (HMG-CoA) synthase, squalene epoxidase and acyl-CoA:cholesterol acyltransferase(ACAT) 1, ACAT 2, small heterodimer partner, and low density lipoprotein receptor (LDLR)-related proteins were significantly changed in the cells.
2009-11-13 | GSE15520 | GEO