Butyrate protects against diet-induced liver fibrosis and suppresses non-canonical TGF-β signaling in human stellate cells
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ABSTRACT:
PROVIDER: PRJNA743538 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15035428_1.fastq.gz | Fastqsanger.gz | |||
| SRR15035428_2.fastq.gz | Fastqsanger.gz | |||
| SRR15035429_1.fastq.gz | Fastqsanger.gz | |||
| SRR15035429_2.fastq.gz | Fastqsanger.gz | |||
| SRR15035430_1.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, the main determinant of NASH-associated mortality. The short chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remains unclear. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.
2021-12-21 | GSE179395 | GEO
Project description:In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.
| S-EPMC8698820 | biostudies-literature
Project description:Butyrate protects pancreatic beta cells from cytokine induced dysfunction
| PRJNA747813 | ENA
Project description:Beta cell dysfunction, caused by metabolic and inflammatory stress, contributes to the development of type 2 diabetes. Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on IL-1β-induced β cell dysfunction. We showed that long-term exposure of mouse islets to non-cytotoxic concentrations of IL-1β impaired insulin secretion and content and reduced proliferation. This dysfunction was prevented when the islets were exposed to butyrate and butyrate alone also boosted insulin secretion. In contrast, butyrate further downregulated the proliferation. To get a better indication of mechanisms of actions we investigated the global mRNA expression profiles using RNA sequencing. Our results indicated that the protective effects of butyrate are associated with upregulation of secretion/transport-related genes and downregulation of inflammatory genes induced by IL-1β. In addition, several cell cycle related genes were strongly inhibited by butyrate. In conclusion, butyrate plays an essential role in supporting beta cell function under inflammatory conditions, suggesting a potential for therapeutic use in treatment and prevention of T2D.
2021-09-27 | GSE180317 | GEO
Project description:Abstract: Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however it remains unclear whether individual BCAAs can attenuate already established NASH and oxidative-inflammatory stress associated with it. Therefore, mice were first put on a run-in fast food diet (FFD) for 26 weeks, these obese mice were then treated with individual BCAAs valine or isoleucine (3% of FFD) for another 12 weeks and compared to FFD controls. Valine and isoleucine treatment did not affect obesity, dyslipidemia, gut permeability or fecal fatty acid excretion, although significantly reduced hyperinsulinemia compared with FFD. Valine and isoleucine significantly reduced ALT, CK-18M30, and liver steatosis with a particularly pronounced effect on the microvesicular component (-61% by valine and -71% by isoleucine). Hepatic 4-hydroxynonenal (4-HNE) immunoreactivity, a marker for oxidative stress-induced lipid peroxidation, was also significantly decreased. Functional genomics analysis demonstrated that valine and isoleucine upregulated BCAA metabolism, deactivated master regulators of anabolic pathways related to steatosis (e.g. SREBPF1) and activated master regulators of mitochondrial biogenesis (e.g. PPARGC1a) and lipid catabolism (e.g. ACOX1, AMPK). The correction of critical metabolic pathways by valine and isoleucine was accompanied by a significant decrease of liver inflammation, and suppression of many FFD-stimulated cytokine and chemokine pathways including IL-1β, TNFα and CCR2 signaling. In conclusion, the dietary intervention with either valine or isoleucine corrected multiple metabolic processes in liver and reduced steatosis and inflammation with profound effects on oxidative stress and inflammatory pathways. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.
2022-06-30 | GSE195798 | GEO
Project description:Background and Aims: Transforming growth factor (TGF-β) induced activation of quiescent hepatic stellate cells (HSC) and their transformation to myofibroblasts is a key event in liver fibrosis and portal hypertension. GIPC (also referred to as synectin) is a downstream signal activation molecule of TGF-β and other receptors. In this study, we sought to identify novel genes targeted by TGF-β and GIPC and elucidate if and how they may contribute to liver fibrosis. Methods and Results: We performed sequential mRNA sequencing analysis on TGF-β stimulated HSC and then on TGF-β-stimulated HSC in presence and absence of GIPC knockdown. IGFBP-3, an insulin growth factor transport protein, emerged as a top activation target of both TGF-β and GIPC, which was confirmed by qPCR, ELISA and Western blot (WB) analysis. Targeted chromatin immunoprecipitation (ChIP) revealed that GIPC increases the histone 3 lysine 27 (H3K27) acetylation activating mark and concurrently decreases the H3K27 inhibitory trimethylation (H3K27m3) mark providing an epigenetic correlate to the gene regulation changes. In vivo, global knockout of IGFBP-3 mice resulted in attenuation of HSC activation markers and attenuation of portal pressure in response to chronic liver injury models. Analysis of serum levels from cirrhotic patients also showed IGFBP-3 increase of more than 2-fold compared to healthy controls. Finally, in vitro mechanism studies revealed that IGFBP-3 promotes HSC migration through integrin dependent phosphorylation of AKT. Conclusion: TGF-β upregulates IGFBP-3 through GIPC leading to increased HSC migration in vitro and promotes portal hypertension in vivo. These studies support the role of IGFBP-3 as a potential pathophysiologic target or biomarker in chronic liver disease.
2020-05-28 | GSE151251 | GEO
Project description:RNA-seq from human hepatic stellate cells treated with TGF-β
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Project description:Hepatic stellate cells (HSCs) in the tumor microenvironment play a pivotal role in the development of hepatocellular carcinoma (HCC), which is the major form of primary liver cancers and one of the most lethal cancer types worldwide. TGF-β and Hippo signaling are two critical pathways regulating HSC activation and HCC development through their downstream transcriptional regulators, i.e., Smad proteins and YAP/TEADs, respectively. However, how the two pathways coordinately exert their functions in HCC remains elusive. In this study, we performed integrated analyses of public liver cancer databases and clinical cancer tissues, leading to identification of CYR61 as one of the key candidate genes that may regulate liver cancer progression. TGF-β-activated Smad2/3 and YAP/TEAD4 can form a protein complex to induce CYR61 expression in both cancer cells and stellate cells. As a secreted matricellular protein, CYR61 exerts its tumor suppressor functions via acting on cancer cells directly or regulating the stromal stellate cells. On one hand, CYR61 ameliorates TGF-β- or YAP-mediated liver cancer cell proliferation, colony formation and invasion in vitro, and also tumor growth in nude mice. On the other, CYR61 also impedes cancer cell- or TGF-β-induced stellate cell activation, thereby mitigating the tumor-promoting functions of HSCs as assessed both in vitro and in vivo. In support of its tumor suppressor function, the expression of CYR61 is reduced in HCC tissues and cell lines when compared with their normal counterparts, which is associated with a shorter survival period in cancer patients. Together, these results add new evidence for the interplay between TGF-β and Hippo signaling in regulating gene transcription, and unveil a pivotal role of CYR61 in suppressing liver cancer progression by controlling the activation of hepatic stellate cells in the tumor microenvironment.
2023-01-11 | GSE222402 | GEO
Project description:We aimed to study the impact of bacteria-derived metabolites in solid organ transplantation. The short-chain fatty acid butyrate was administered using a new drug-delivery method developed by Wang et al. (https://doi.org/10.1038/s41551-022-00972-5). This system is based on a micelle platform that carries and protects butyrate (ButM) from degradation in the upper gastrointestinal tract, to lower distal portions of the gut. Mice (adult B6 females) were treated for 21 days with ButM (100mg/mL) or 1x PBS. Splenic Ly6Chi CD11b+ monocytes were sorted for bulk RNAseq using the Takara SMART-Seq mRNA LP and Unique Dual Index kits. Libraries were sequenced using the Illumina NovaSeq 6000 platform.
2024-04-05 | E-MTAB-13931 | biostudies-arrayexpress
Project description:Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibro-genesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Re-al-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The re-leasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interac-tions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the potential of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting the promising role of β-CIT in anti-hepatic fibrosis therapies.
2024-08-06 | PXD052806 | Pride