Cellular Communication Networks in Fibrosis: Single-nucleus Transcriptomic Insights from the MAFLD Pig Model
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PROVIDER: PRJNA1048073 | ENA |
REPOSITORIES: ENA
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Project description:The aim of this research is to reveal the cellular crosstalk in fibrosis liver using transgenic pigs (TG) expressing humanized risk genes (PNPLA3I148M-GIPRdn-hIAPP) as a MAFLD model. The study uses single-nucleus sequencing to reveal the differentiation and interaction characteristics of various cell populations in the liver during the development of MAFLD. Compared to wild-type pigs (WT), the model pigs showed significantly increased plasma levels of neurotensin and phosphatidylserine, along with insulin resistance and significantly decreased HDL-c levels. After 6 months of high-fat high-sucrose diet induction, the model pigs exhibited obvious liver pathological features, including fat deposition, inflammatory cell aggregation, fibrosis, and blocked insulin signaling pathways. Single-nucleusl transcriptome sequencing identified six main cell types in the liver, and correlation analysis showed similar liver cell clusters, zones, and functions between pigs and humans. Liver cells near the central vein and liver sinusoidal endothelial cells (LSECs) were sensitive to metabolic changes and exhibited impaired function and reduced numbers first. Fibrosis-related pathways and the Rap1 pathway were activated in hepatic stellate cells of the model pigs, while retinol metabolism decreased, and the number of activated hepatic stellate cells increased. The differentiation direction of macrophages in the model pig's liver was markedly different from that in the WT pigs; the former differentiated toward the M1 phenotype, showing high expression of MHC-II antigen presentation molecules, various cytokines, phagosomes, and lysosomal-related genes. In contrast, the macrophages in the WT pig's liver primarily differentiated toward the M2 phenotype and expressed genes related to immune regulation and injury repair. There was active cell interaction between hepatic stellate cells, endothelial cells, and M1-type macrophages, promoting the development of chronic inflammation and fibrosis through interactions of receptors such as FGFs-FGFRs, PDGFs-PDGFRs, EFNA1-EPHRs, and CXCL12-CXCR4/CXCR7.In conclusion, the transgenic pig model of MAFLD exhibits liver pathological features consistent with MAFLD patients. The receptor interactions between hepatic stellate cells, endothelial cells, and macrophages play a key role in regulating metabolic inflammation and fibrosis development. Remarkable changes in receptor interactions hold promise for application in MAFLD drug development.
2024-12-31 | GSE249237 | GEO
Project description:MAFLD is a heterogenous spectrum disorder affecting 20% of the population. Inflammatory processes contribute to various stages of MAFLD and thought to instigate hepatic fibrosis. For this reason, targeting inflammation has been heavily nominated as an approach to mitigating liver fibrosis. Lipopolysaccharide binding protein is a secreted protein that plays an established role in innate immune responses. In a murine model of MAFLD, we used a liver-specific deletion of LBP model to study its role in hepatic inflammation. Single nucleus RNA-seq were applied to investigate the role of LBP in hepatic cell composition.
2024-07-15 | GSE254626 | 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:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.
2022-06-21 | GSE198173 | GEO
Project description:This trial examines cancer communication within Hispanic social networks. Hispanics have the lowest colorectal cancer screening rate of any major ethnic group and health interventions are crucially needed among Hispanics. Patient decision aids are health communication interventions designed to provide patients with targeted health information and have shown to improve colorectal cancer screening rates among Hispanics. The goal of this study is to investigate, in a sample of Hispanics, how a colorectal cancer decision aid aimed at increasing individuals’ colorectal cancer screening behavior has effects on their alters’ intention to get screened for colorectal cancer.
| 2343521 | ecrin-mdr-crc
Project description:Retrograde response was widely studied in budding yeast but the main transcription factors that transmit it (RTG1,2 and 3) are not conserved in other organisms, thus it is interesting to study how communication between mitochondria and nucleus evolved in distantly related fission yeast, and which are the common aspects of this conserved pathway between yeast and higher organisms.To analyse any retrograde response in fission yeast, we inhibited the electron transport chain activity by antimycin A and studied cellular gene expression changes by microarrays. Cells treated with antimycin A in fermentative medium (YE with 3% glucose), showed the same growth rate as untreated cells, but they reached a lower biomass in stationary phase. Antimycin A treated cells consumed glucose at a faster rate and produced more ethanol, indicating that the energy metabolism was shifted even more towards fermentation. We analyzed the transcriptomes of antimycin A-treated cells to untreated control cells during early exponential growth phase (OD 0.5).
2016-11-01 | E-MTAB-4520 | biostudies-arrayexpress
Project description:Hepatic lipopolysaccharide binding protein uncouples inflammation from fibrosis in MAFLD
| PRJNA1071160 | ENA
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/
2022-08-02 | PXD032214 | Pride
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/
2022-08-02 | PXD032211 | Pride
Project description:A constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer, resulting in proliferative advantages for cancer cells, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1 KO and parental cells show that IQGAP1 KO alters a specific AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1 KO cells, CI intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1 KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer.
2023-08-04 | PXD038314 | Pride