Mouse
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413375 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6132650_1.fastq.gz | Fastqsanger.gz | |||
| SRR6132650_2.fastq.gz | Fastqsanger.gz | |||
| SRR6132660_1.fastq.gz | Fastqsanger.gz | |||
| SRR6132660_2.fastq.gz | Fastqsanger.gz | |||
| SRR6132651_1.fastq.gz | Fastqsanger.gz |
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Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and regulates bile acid metabolism, glucose and cholesterol homeostasis. From mouse studies we know that the novel FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver, but there is currently no data on the effects of OCA on human liver gene expression. This is especially relevant since the novel FXR agonist OCA is currently tested in clinical trials for the treatment of several diseases, such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and Type 2 Diabetes. In this study we investigate the effect of OCA treatment on gene expression profiles and localization of FXR to the genome in relevant liver samples. ChIP-Seq for FXR in Liver tissue from 2 male mice treated with OCA/INT-747 (10mg/kg/day) and 2 male mice treated with vehicle (1% methyl cellulose).
2016-01-27 | E-GEOD-73624 | biostudies-arrayexpress
Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.
2022-09-23 | GSE184261 | GEO
Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.
2022-09-23 | GSE184055 | GEO
Project description:Farnesoid X receptor (FXR) is a ligand activated nuclear receptor belonging to the nuclear receptor superfamily. Bile acids (BAs) are the endogenous ligand for FXR. FXR is a master regulator of BA homestasis, including BA synthesis, metabolism, transport, and enterohepatic circulation of BAs. Besides, FXR is involved in regulating diverse physioligical function in both humans and mice. GW4064 is a synthetic FXR agonist which selectively activates FXR and induce the transcription of FXR target genes.
2014-07-24 | GSE57305 | GEO
Project description:Obstruction of bile flow results in bacterial proliferation and mucosal injury in the small intestine that can lead to the translocation of bacteria across the epithelial barrier and systemic infection. These adverse effects of biliary obstruction can be inhibited by administration of bile acids. Here we show that the farnesoid X receptor (FXR), a nuclear receptor for bile acids, induces genes involved in enteroprotection and inhibits bacterial overgrowth and mucosal injury in ileum caused by bile duct ligation. Mice lacking FXR have increased ileal levels of bacteria and a compromised epithelial barrier. These findings reveal a central role for FXR in protecting the distal small intestine from bacterial invasion and suggest that FXR agonists may prevent epithelial deterioration and bacterial translocation in patients with impaired bile flow. In this report we have examined the role of FXR in the ileum. We demonstrate that it plays a crucial role in preventing bacterial overgrowth and maintaining the integrity of the intestinal epithelium
2012-07-19 | GSE39507 | GEO
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and regulates bile acid metabolism, glucose and cholesterol homeostasis. From mouse studies we know that the novel FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver, but there is currently no data on the effects of OCA on human liver gene expression. This is especially relevant since the novel FXR agonist OCA is currently tested in clinical trials for the treatment of several diseases, such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and Type 2 Diabetes. In this study we investigate the effect of OCA treatment on gene expression profiles and localization of FXR to the genome in relevant liver samples.
2016-01-27 | GSE73624 | GEO
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:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA approved treatments, but farnesoid X receptor (FXR) agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet (HFD) and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that HFD-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.
2023-01-05 | GSE222171 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA approved treatments, but farnesoid X receptor (FXR) agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet (HFD) and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that HFD-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.
2023-01-11 | GSE222499 | GEO
Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.
2022-07-06 | GSE193860 | GEO