Benzbromarone exacerbates high-fat-induced lipid accumulation in primary hepatocytes by activating PPARγ [OA]
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PROVIDER: PRJNA1146080 | ENA |
REPOSITORIES: ENA
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Project description:Objective: Benzbromarone (BBR) is an effective uric acid-lowering drug, and studies have shown that BBR can exacerbate hepatic steatosis in obese individuals. However, the underlying mechanisms remain unclear. Methods: Primary hepatocytes isolated from C57/BL6 mice were cultured in vitro, and a high-fat culture model was simulated with 20mM oleic acid (OA) treatment. OA and bovine serum albumin (BSA) were mixed at a ratio of 1:4, pre-treated at 37°C for 1-2 hours, and then co-incubated with primary hepatocytes for 16 hours. The in vitro experiments were divided into four groups: control (BSA), control treatment group (BSA+BBR), high-fat group (OA), and high-fat treatment group (OA+BBR). After 16 hours of treatment, intracellular triglyceride (TAG) content was measured, and Bodipy staining was used to observe the number and morphological changes of lipid droplets. RNA-seq analysis was conducted to assess changes in the gene expression profile of hepatocytes with BBR treatment under BSA and OA conditions. Results: BBR significantly increased the intracellular TAG content in primary hepatocytes treated with OA, while no significant increase was observed in the BSA treatment group. Bodipy staining experiments also confirmed that BBR led to an increase in the number and size of lipid droplets under OA treatment. Transcriptomic data revealed that under both BSA and OA conditions, BBR upregulated the expression of a large number of genes related to lipid synthesis, which were associated with the activation of the PPARγ signaling pathway. Conclusion: BBR promotes the expression of genes involved in lipid synthesis in primary hepatocytes by activating PPARγ, leading to specific hepatic lipid accumulation under high-fat conditions.
2025-01-29 | GSE274374 | GEO
Project description:Objective: Benzbromarone (BBR) is an effective uric acid-lowering drug. However, it can induce severe liver damage in some patients. Studies have shown that BBR specifically exacerbates hepatic steatosis in obese individuals, leading to aggravated liver injury. The exact mechanism behind this phenomenon remains unclear. Methods: db/db mice were divided into four groups: Control, BBR administration (BBR), Pparg knockdown (Pparg-KD), and BBR administration with Pparg knockdown (BBR + Pparg-KD). One week after AAV8-shRNA-Pparg virus injection, mice were orally administered BBR for four weeks, and changes in blood glucose and body weight were measured. Subsequently, samples were collected, and plasma lipid levels, hepatic lipid content, and liver function parameters were determined. RNA-seq was performed to assess changes in the hepatic gene expression profile and analyze the protective effect of PPARγ knockdown on BBR-induced drug-induced liver injury. Results: Mice in the BBR group exhibited more severe levels of plasma lipids, hepatic lipids, and liver function parameters compared to the Control group. However, mice in the BBR + Pparg-KD group showed significant improvements in these indicators compared to the BBR group. Transcriptomic analysis revealed that BBR administration upregulated the expression of various lipid synthesis-related genes, primarily associated with the PPAR signaling pathway. Furthermore, PPARγ knockdown reversed the increased expression of these lipid synthesis genes. This suggests that PPARγ knockdown has a significant protective effect against BBR-induced drug-induced liver injury. Conclusion: Hepatocyte-specific knockdown of PPARγ can protect against BBR-induced exacerbation of hepatic steatosis and liver injury by inhibiting the promotion of lipid synthesis through PPARγ activation.
2025-01-29 | GSE274748 | GEO
Project description:Chromatin immunoprecipitation-Sequence (ChIP-Seq) analysis indicated increased binding of PPARγ to Srebf1 promoter region after activating iNKT cells, and that was inhibited by T007—PPARγ inhibitor .
2021-05-31 | GSE131908 | GEO
Project description:Here we report, for the first time, the acute effects of the synthetic PPARγ agonist rosiglitazone on the transcriptional network of PPARγ in adipocytes. Treatment with Rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by genome-wide RNA polymerase II occupancy. Unlike what has been shown for many other nuclear receptors, agonist treatment does not lead to major changes in the occurrence of PPARγ binding sites. However, rosiglitazone promotes PPARγ occupancy at many preexisting sites, and this is paralleled by increased occupancy of the mediator subunit MED1. The increase in PPARγ and MED1 binding is correlated with an increase in transcription of nearby genes indicating that rosiglitazone, in addition to activating the receptor, also promotes its association with DNA, and that this is causally linked to recruitment of mediator and activation of genes. Notably, both Rosiglitazone-activated and -repressed genes are induced during adipogenesis. However, Rosiglitazone-activated genes are markedly more associated with PPARγ than repressed genes and are highly dependent on PPARγ for expression in adipocytes. By contrast, repressed genes are associated with the other key adipocyte transcription factor CCAAT-Enhancer binding protein (C/EBPα), and their expression is more dependent on C/EBPα. This suggests that the relative occupancies of PPARγ and C/EBPα are critical for whether genes will be induced or repressed by PPARγ agonist. Examination of binding of PPARγ, C/EBPα, RNAPII, CBP and MED1 in mature 3T3-L1 adipocytes treated with 1 μM Rosiglitazone and/or 0.1% DMSO for 1 hour.
2013-08-01 | E-GEOD-49423 | biostudies-arrayexpress
Project description:Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPARγ. In contrast to existing synthetic PPARγ drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPARγ activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPARγ is involved in.
2012-05-02 | GSE28384 | GEO
Project description:Knockdown of PPARγ can ameliorate benzbromarone-induced obesity-specific drug-induced liver injury
| PRJNA1147752 | ENA
Project description:Angiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short chain fatty acids (SCFA). Induction of ANGPTL4 by SCFA cannot be mimicked by the histone deacetylase inhibitor Trichostatin A. SCFA induce ANGPTL4 by activating the nuclear receptor PPARγ, as shown by use of PPARγ antagonist, PPARγ knock-down, and transactivation assay, which shows activation of PPARγ but not PPARα and PPARδ. At concentrations required for PPARγ activation and ANGPTL4 induction in colonocytes, SCFA do not stimulate PPARγ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPARγ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modelling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin was associated with induction of PPAR target genes and pathways in the colon, as shown by microarray and subsequent gene set enrichment analysis. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes; 2) SCFA transactivate and bind to PPARγ by serving as selective PPAR modulators. Our data point to activation of PPARγ as a novel mechanism of gene regulation by SCFA in the colon.
2013-03-11 | GSE43065 | GEO
Project description:The peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with PPARγ function cause lipodystrophy. Structural studies indicate that PPARγ domains engage in several intra- and inter-moleuclar interactions; however, how these interactions modulate the ability of PPARγ to activate target genes in a cellular context is currently poorly understood. Here we analysed the transcriptional potential of R212Q and E379K two previously uncharacterised lipodystrophy-associated PPARγ mutants that are located in distinct PPARγ domains but are both predicted to affect intermolecular interactions. Using a combination of biochemical and genome-wide approaches we show that these mutations impair binding to an overlapping subset of enhancers that are less accessible and specifically require PPARγ for chromatin remodeling. Based on these findings we propose a model in which recruitment of PPARγ to chromatin is determined by several intermolecular interfaces. Furthermore, our data exemplify that relatively subtle molecular defects in transcription factors are sufficient to significantly affect enhancer binding and thereby transcriptional output.
2022-09-08 | PXD036589 | Pride
Project description:Transcriptional profiling of Acinetobacter baumannii ATCC17978 cells comparing treated ethanol cells with oleanolic acid treated. Based on the gene expression, we performed experiments to confirm the therapeutic effect and mechanism of OA in A. baumannii. We performed a transcriptome anaylsis of 2 samples that are OA and ethanol treatment, respectively.
2014-08-09 | E-GEOD-60239 | biostudies-arrayexpress
Project description:Here we report, for the first time, the acute effects of the synthetic PPARγ agonist rosiglitazone on the transcriptional network of PPARγ in adipocytes. Treatment with Rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by genome-wide RNA polymerase II occupancy. Unlike what has been shown for many other nuclear receptors, agonist treatment does not lead to major changes in the occurrence of PPARγ binding sites. However, rosiglitazone promotes PPARγ occupancy at many preexisting sites, and this is paralleled by increased occupancy of the mediator subunit MED1. The increase in PPARγ and MED1 binding is correlated with an increase in transcription of nearby genes indicating that rosiglitazone, in addition to activating the receptor, also promotes its association with DNA, and that this is causally linked to recruitment of mediator and activation of genes. Notably, both Rosiglitazone-activated and -repressed genes are induced during adipogenesis. However, Rosiglitazone-activated genes are markedly more associated with PPARγ than repressed genes and are highly dependent on PPARγ for expression in adipocytes. By contrast, repressed genes are associated with the other key adipocyte transcription factor CCAAT-Enhancer binding protein (C/EBPα), and their expression is more dependent on C/EBPα. This suggests that the relative occupancies of PPARγ and C/EBPα are critical for whether genes will be induced or repressed by PPARγ agonist.
2013-08-01 | GSE49423 | GEO