Effect of Tormentic Acid on metabolic-associated fatty liver disease in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222807 | GEO | 2023/01/18
REPOSITORIES: GEO
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Project description:Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MALFD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analyzed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n=3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells (KC) and monocyte-derived macrophages (MdM). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocytes/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis we demonstrate recruitment of MdMs precedes KC loss and liver damage and that MdMs may serve a role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans and this occurs prior to changes in KC number. MdMs appear to have a role in lipid uptake during early stages of MALFD.
2023-10-01 | GSE235079 | GEO
Project description:Background Metabolic associated fatty liver disease (MAFLD) was recently proposed to replace non-alcoholic fatty liver disease (NAFLD), which is defined as ectopic fat deposition in the liver. Hepatic steatosis is an independent predictor for insulin resistance and cardiovascular risk and hence mortality. The aim of present study was to investigate the urine molecular pattern and potential urine biomarker to distinguish healthy control, mild and severe hepatic steatosis in MAFLD patients using proteomic data. Method Hepatic steatosis was measured by Magnetic resonance imaging (MRI) that measure the proton density fat fraction (MRI-PDFF). Proteomic measurements of urine samples were done by mass spectrometry. Linear regression analyses were used to detect significant associations between the biomarkers and clinical parameters. Western blot and Elisa were performed for validation. Results Multiple pathways have been compromised in MAFLD, including the carbohydrate derivative catabolic process, glycosaminoglycan process, aminoglycan metabolic process, inflammatory response, insulin-like growth factor receptor and GTPase complex. Alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin were finally identified to be potential urine biomarkers to detect mild/severe hepatic steatosis.
2022-08-12 | PXD026333 | Pride
Project description:The breakdown of toll-like receptor (TLR) tolerance results in tissue damage. Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a crucial negative regulator of TLR signaling. MBOAT7 deficiency in macrophages as observed in patients with metabolic (dysfunction) associated fatty liver disease (MAFLD) and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can be exploited as a therapeutic target for diseases associated with dysregulation of the TLR signaling cascade.
2022-10-21 | GSE204964 | GEO
Project description:The breakdown of toll-like receptor (TLR) tolerance results in tissue damage. Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a crucial negative regulator of TLR signaling. MBOAT7 deficiency in macrophages as observed in patients with metabolic (dysfunction) associated fatty liver disease (MAFLD) and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can be exploited as a therapeutic target for diseases associated with dysregulation of the TLR signaling cascade.
2022-10-21 | GSE204963 | GEO
Project description:The breakdown of toll-like receptor (TLR) tolerance results in tissue damage. Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a crucial negative regulator of TLR signaling. MBOAT7 deficiency in macrophages as observed in patients with metabolic (dysfunction) associated fatty liver disease (MAFLD) and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can be exploited as a therapeutic target for diseases associated with dysregulation of the TLR signaling cascade.
2022-10-21 | GSE204962 | GEO
Project description:This study aimed to investigate the effects and underlying mechanisms of tormentic acid (TA) on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. The rats were intragastrically administered with 50% CCl4 for 9 weeks to induce hepatic fibrosis, followed by various agents for 6 weeks. Transcriptomic analysis was carried out to predict the potential targets, and then multiple examinations were performed to verify the prediction. The results showed that TA significantly alleviated liver injury and fibrosis, as evidenced by the ameliorative pathological tissue, low transaminase activity, and decreased collagen accumulation. Besides, TA markedly reduced hepatocyte apoptosis by regulating the expression of caspase-3 and Bcl-2 families. The transcriptomic analysis revealed 2,173 differentially expressed genes (DEGs) between the TA and model groups, which could be enriched in the metabolic pathways and the PI3K/Akt and NF-κB signaling pathways. The metabolomics analysis showed that TA could regulate the glycerophospholipid metabolism pathway by regulating the synthesis of phosphatidylserines, phosphatidylethanolamines and phosphatidylcholines. Moreover, the integrative analysis of the transcriptomics and metabolomics data indicated that TA inhibited the glycerophospholipid metabolism pathway by inhibiting the expression of LPCAT4, PTDSS2, PLA2G2A and CEPT1. In addition, the relevant signaling pathways analysis confirmed that TA inhibited HSCs activation by blocking the PI3K/Akt/mTOR pathway and ameliorated inflammatory injury by inhibiting the NF-κB pathway. In conclusion, TA significantly alleviates liver fibrosis in vivo by inhibiting the glycerophospholipid metabolism pathway and the PI3K/Akt/mTOR and NF-κB signaling pathways.
2021-11-13 | GSE188604 | GEO
Project description:Metabolic-associated fatty liver disease (MAFLD) comprises a spectrum of clinical entries ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of non-alcoholic steatohepatitis (NASH) that may lead to fibrosis and hepatocellular carcinoma. What triggers inflammation in MAFLD is unknown. We find that lipid accumulation in hepatocytes induces expression of ligands for the activating immune receptor NKG2D. Tissue-resident innate-like T cells are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit pro-inflammatory cells into the liver, causing NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in a dietary model for NASH and had a marked decrease in the incidence of hepatic tumors. Importantly, the frequency of IL-17A+ γδ T cells in the blood MAFLD patients correlated with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in context of MAFLD.
2022-04-11 | GSE200482 | GEO
Project description:Transcriptomic analysis was applied to liver tissues of seven patients with MAFLD and nine normal controls,then, differential genes were identified by comparative analysis of sequencing results, and target genes that may be related to the pathogenesis of MAFLD were further studied.This study may provide new ideas for understanding the pathogenesis of MAFLD and thus provide new targets for the treatment of MAFLD.
2021-12-14 | GSE183229 | GEO
Project description:This study aimed to investigate the effects and underlying mechanisms of sarsasapogenin (SAR) on dietary methionine choline deficiency induced non-alcoholic fatty liver disease in mice, The differentially expressed genes in liver tissue in “Normal VS model ”and “Model VS SAR” were identified by RNA-seq.
2023-01-20 | GSE222935 | GEO
Project description:Bone marrow mesenchymal stem/stromal cells (BMSCs) can be transformed into tumor-associated MSCs (TA-MSCs) within the tumor microenvironment to facilitate tumor progression. However, the underline mechanism and potential therapeutic strategy remain unclear. Here, we explored that interleukin 17 (IL-17) cooperating with IFNγ transforms BMSCs into TA-MSCs, which promotes tumor progression by recruiting macrophages/monocytes and myeloid-derived suppressor cells (MDSCs) in murine melanoma. IL-17 and IFNγ transformed TA-MSCs have high expression levels of myelocyte-recruiting chemokines (CCL2, CCL5, CCL7, and CCL20) mediated by activated NF-κB signaling pathway. Furthermore, retinoic acid inhibits NF-κB signaling, decreases chemokine expression, and suppresses the tumor-promoting function of transformed TA-MSCs by prohibiting the recruitment of macrophages/monocytes and MDSCs in the tumor microenvironment. Overall, our findings demonstrate that IL-17 collaborating with IFNγ to induce TA-MSC transformation, which can be targeted by RA for melanoma treatment.
2021-03-19 | GSE169145 | GEO