TSPO ameliorated the liver fibrosis in non-alcoholic fatty liver disease mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE138666 | GEO | 2021/04/04
REPOSITORIES: GEO
Similar Datasets
Project description:Translocator Protein (18kDa, TSPO) is a mitochondria outer membrane transmembrane protein and which expression is elevated during inflammation and injury. However, the exact function of TSPO is still controversial. Here, we constructed TSPO global knockout (KO) mice by Cre-LoxP system independently, which abolished TSPO protein expression in all tissues and shown normal phenotypes. The birth rate of TSPO heterozygote (Het)/Het breeding was consistent with the Mendel’s Law, suggesting a normal viability of TSPO KO mice at birth. RNAseq analysis showed no significant difference in the gene expression profile of lung tissues from TSPO KO mice compared with that of wild type mice, even the genes associated with bronchial alveoli immune homeostasis. The alveolar macrophage population was also not affected by TSPO deletion in the physiological condition. Our findings contradicts the results of Papadopoulos, but confirmed Selvaraj’s findings. This study reveals TSPO deficiency does not affect the viability and bronchial alveoli immune homeostasis.
2016-12-08 | GSE84942 | GEO
Project description:The mitochondrial translocator protein (TSPO) has been shown to bind cholesterol with high affinity and is involved in mediating its availability for steroidogenesis. We recently reported that targeted Tspo gene deletion in MA-10 mouse tumor Leydig cells resulted in reduced cAMP-stimulated steroid formation and significant reduction in the mitochondrial membrane potential (ΔΨm) compared to control cells. We hypothesized that ΔΨm reduction in the absence of TSPO probably reflects the dysregulation and/or maintenance failure of some basic mitochondrial function(s). To explore the consequences of TSPO depletion via CRISPR-Cas9-mediated deletion (indel) mutation in MA-10 cells, we assessed the transcriptome changes in TSPO-mutant versus wild-type (Wt) cells using RNA-seq. Gene expression profiles were validated using real-time PCR. We report herein that there are significant changes in nuclear gene expression in Tspo mutant versus Wt cells. The identified transcriptome changes were mapped to several signaling pathways including the regulation of membrane potential, calcium signaling, extracellular matrix, and phagocytosis. This is a retrograde signaling pathway from the mitochondria to the nucleus and is probably the result of changes in expression of several transcription factors, including key members of the NF-κB pathway. In conclusion, TSPO regulates nuclear gene expression through intracellular signaling. This is the first evidence of a compensatory response to the loss of TSPO with transcriptome changes at the cellular level.
2021-01-09 | GSE164481 | GEO
Project description:Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor for hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation; meanwhile, sequentially developed fatty liver, NASH, and cirrhosis/HCC in a diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that play a key role in the NASH-dependent HCC development. Overall, we established a new mouse model that develops NASH-dependent HCC and provides a promising approach to improve the treatment.
2022-06-02 | E-MTAB-9973 | biostudies-arrayexpress
Project description:Dyslipidemia and inflammation play key roles in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. NAFLD, particularly its severe form nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease (CVD) risk. HDL (high density lipoprotein- also a CVD risk) are decreased in NAFLD but whether HDL function is abnormal in NAFLD is unknown. Furthermore, it is unknown whether dyslipidemia contributes to reduced HDL function in NAFLD and whether hepatic inflammation further impairs HDL function in patients with NASH. Therefore, the aim of this study was to investigate HDL function and to examine the effect of dyslipidemia and inflammation on HDL metabolism in patients with biopsy-proven simple steatosis (SS) and NASH. RESULTS: Compared to controls, SS and NASH subjects had significantly higher levels of plasma triglyceride, insulin, and were more insulin resistant (HOMA, P<0.05) with no differences in total cholesterol, HDL cholesterol, ApoB100 and ApoAI levels. NAFLD patients had increased production and degradation rates of both HDLc and ApoAI that resulted in their levels remaining stable. The degradation rates also were increased of other HDL proteins, including ApoAII, ApoAIV, vitamin D-binding protein, and complement 3 (all P<0.05). NAFLD patients had increased activities of LCAT and CETP, indicating altered HDL lipidation. NAFLD induced alterations in HDL metabolism were associated with reduced anti-oxidant but increased pro-inflammatory activity of HDL. However, no differences were observed in either HDL function or the kinetics of HDLc and HDL proteins between SS and NASH subjects.
2019-08-12 | PXD010199 | Pride
Project description:We hypothesized that the potential ability of the 18 kDa mitochondrial translocator protein (TSPO) to regulate gene expression may underlie its numerous reported functions, ranging from mitochondrial activity till mental disorders. Therefore, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 1 hr the TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. After 24 hrs primarily gene expression for enzymes and other proteins is changed. The associated gene products are known to affect various cellular functions: programmed cell death, cell cycle, viability, proliferation, migration, differentiation, development, tumorigenesis, and inflammatory / immune responses. Our microscopic studies showed intense TSPO mitochondrial labeling but no TSPO signal in the cell nuclei. Thus, it appears that the TSPO is part of the retrograde mitochondrial-nuclear signaling pathway for modulation of gene expression and thereby may exert its numerous effects on cell function, phenotype, and disease. U118MG cells (1.255 à 106) were seeded in Petri dishes (i.e. 28.5 à 103 cells / cm2) and allowed to proliferate for 3 days in full medium. Experiments for gene expression assayed with microarray typically consisted of three experimental groups and a vehicle control group (n = 3 for each group). Serum deprived medium was applied for 24 hrs, in the experimental groups ending with the inclusion a choice of various PK 11195 exposures i.e. either 1 hr, 3 hrs, or 24 hrs. Exposure to PK 11195 implies serum deprived medium with 1% alcohol (vehicle) and PK 11195 (25 µM final concentration) for the required time period. 25 µM of PK 11195 is the optimal concentration for these types of experiments with U118MG cells (Kugler et al., 2008). The cells were collected by trypsinization, washed by centrifugation in phosphate buffered saline (PBS) (400 à g, 5 min), and lysed [RLT lysis buffer provided with the RNeasy Mini Kit diluted with β-mercaptoethanol (1 : 100)], according to the manufacturer's instructions. Lysates were stored at -70oC.
2016-02-18 | E-GEOD-77998 | biostudies-arrayexpress
Project description:This study was intended to dissect the role of PBR/TSPO in hepatic metabolism. As it was determined that the purported role for PBR/TSPO in steroidogenesis was a misconception, the precise function and regulation of this therapeutic target remains a mystery. Via examining gene expression changes associated with PBR/TSPO deficiency in the liver, these results evaluate specific phenotypic perturbations linked to PBR/TSPO function.
2024-03-23 | GSE228098 | GEO
Project description:Inhibition of adipocyte triglyceride lipase (ATGL/PNPLA2) activity in insulin resistance and non-alcoholic fatty liver disease is an attractive therapeutic target. This study evaluated the impact of Atglistatin-mediated ATGL inhibition on non-alcoholic steatohepatitis (NASH) development in diabetic and hyperlipidaemic mice. Streptozotocin-injected male mice were fed an HFD to induce NASH. We analysed liver histology, hepatic lipid content, immunohistochemistry, RNA sequencing, and serum biochemistry. Mechanistically, we treated Caco2 cells, human primary ileum-derived organoids, and HepG2 ATGL KD cells with the novel human ATGL inhibitor NG-497 and WY14643. Atglistatin reduced body and liver weights, total liver lipid content, and improved blood sugar levels consistent with improved liver enzymes, histological liver injury, and NAFLD activity scores. Mechanistically, Atglistatin reduced Cpt1a and Abca1, suggesting impaired Ppara signalling that favours hydrophilic bile acids (BA) synthesis since Cyp7a1, Cyp27a1, and Cyp2c70 were increased while Cyp8b1 was reduced. Accordingly, Intestinal lipid transporters, Abca1 and Cd36, were reduced, consistent with the reduction of liver TAG species, mostly linoleic acids. We used human-specific ATGL inhibitor NG-497 to validate the mouse findings. The NG-497-treated human primary ileum organoids and Caco2 cells showed reduced ATGL, ABCA1, FATP5, CD36, and MTTP. PPARa signalling was impaired in the ileum organoids and HepG2 treated with NG-497 and in HepG2 ATGL KD since PPARa, CPT1a, AOX, ABCA1, and CYP8B1 were reduced, and CYP7A1 increased. Inhibition of ATGL activity reduces the availability of ligands for Ppara activation leading to impaired Ppara signalling, which translate into hydrophilic BA that interferes with dietary lipid absorption, improving metabolic disturbances. The validation with the NG-497 should open a new clinical avenue for NAFLD clinical trial and treatment.
2024-11-01 | GSE236832 | GEO
Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.
2014-02-01 | E-GEOD-52748 | biostudies-arrayexpress
Project description:TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing. We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages. In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.
2023-09-14 | GSE230453 | GEO
Project description:Background: The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its non-selective cellular expression pattern implies roles beyond inflammatory processes. The present study investigated whether neuronal activity modifies TSPO expression in the adult central nervous system. Methods: Single-cell RNA sequencing was performed to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, whereas confocal laser scanning microscopy was used to verify TSPO protein in neuronal and non-neuronal cell populations. TSPO RNA and protein were quantified after stimulating neuronal activity with distinct stimuli, including designer receptors exclusively activated by designer drugs (DREADDs), exposure to a novel environment and acute treatment with the psychostimulant drug, amphetamine. Results: Single-cell RNA sequencing demonstrated a non-selective and multi-cellular gene expression pattern of TSPO at basal conditions in the adult mouse hippocampus. Confocal laser scanning microscopy confirmed that TSPO protein is expressed in neuronal and non-neuronal (astrocytes, microglia, vascular endothelial cells) cells of cortical (medial prefrontal cortex) and subcortical (hippocampus) brain regions. Stimulating neuronal activity through chemogenetic (DREADDs), physiological (novel environment exposure) or psychopharmacological (amphetamine treatment) approaches led to consistent increases in TSPO gene and protein levels in neurons but not in microglia or astrocytes. Conclusions: Neuronal activity has the potential to modify TSPO expression in the adult central nervous system. These findings challenge the general assumption that altered TSPO levels unequivocally mirrors ongoing neuroinflammation and emphasize the need to consider non-inflammatory interpretations in some physiological or pathological contexts.
2022-05-01 | GSE150508 | GEO