Therapeutic Inhibition of Inflammatory Monocyte Recruitment Reduces Steatohepatitis and Liver Fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98782 | GEO | 2017/11/13
SECONDARY ACCESSION(S): PRJNA386193
REPOSITORIES: GEO
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2022-01-09 | GSE175448 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease caused by excess fat accumulation, closely associated with obesity and metabolic syndrome.Bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2). Some clinical trials of CDDO-Me were conducted for chronic kidney diseases and pulmonary arterial hypertension, whereas the hepatoprotective effect of CDDO-Me on nonalcoholic steatohepatitis (NASH) has not yet been elucidated. The purpose of this study was to determine the hepatoprotective potential and mechanisms of CDDO-Me in a diet-induced NASH mouse model. Whole transcriptome analysis revealed that CDDO-Me markedly inhibited the expressions of chemokine ligands, Ccl3 and Ccl4, and the chemokine receptors, Ccr1 and Ccr5 that increased in NASH mice while activating Nrf2-dependent pathway. Serum protein levels of CCL3 and CCL4 upregulated in NASH mice were inhibited in a dose-dependent manner by treatment with CDDO-Me. CDDO-Me inhibited the expression levels of Ccr1 and Ccr5, and simultaneously blocked Ccl3 and Ccl4 the ligands of the receptors, respectively in RAW264.7 cell line. Taken together with the observations, CDDO-Me directly inhibits the expression of CCL3-CCR1 and CCL4-CCR5 axes in macrophages of NASH mice, which might contribute to the improvement of nonalcoholic steatohepatitis and fibrosis through the interference of monocyte-derived macrophage migration.
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Project description:Metabolic activation of CD8+ and NKT-cells causes NASH and HCC through cross-talk with hepatocytes. Mice that devloped HCC or NASH were compared to work out genomic differences of the two diseases. In order to characterise the importance of CCR2 (activation of monocytes) in the development of NASH and HCC CCR2 double-mutant mice were compared to CCR2 wildtype mice.
2014-06-01 | E-MTAB-2469 | biostudies-arrayexpress
Project description:Glutaredoxin-1 (Glrx) controls redox signaling and has an anti-apoptotic function. We evaluated the role of Glrx on hepatic cell damage and fibrosis induced by a high-fat diet. We fed mice a high-fat high-fructose diet to induce non-alcoholic steatohepatitis (NASH) and injected AAV-Glrx to express hepatocyte-specific Glrx in diet-induced NASH mice. AAV-Glrx suppressed fibrosis and improved liver function in the NASH liver. We used microarrays to profile gene expression in the NASH liver and find pathways that AAV-Glrx mediated to attenuate fibrosis and NASH progression.
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2019-04-08 | GSE122322 | GEO
Project description:HIV+ Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4+ T cells with resistance specific to R5-tropic HIV, reversed after introduction of CCR5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4+ T cells of these EC/VCs had lower CCR2 and CCR5 mRNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of CCR2 and CCR5, despite having more accessible chromatin by Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq). Other nearby genes were also down-regulated, over a region of ~500kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with CCR2/CCR5 down-regulation, suggesting that the phenotype is heritable.
2019-04-08 | GSE122321 | GEO
Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.
2013-04-02 | E-GEOD-37031 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.
2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress
Project description:Background/Aims: There is a major unmet need to assess prognostic impact of anti-fibrotics in clinical trials due to the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. Methods: A Fibrosis Progression Signature (FPS) was defined to predict fibrosis progression within 5 years in HCV and NAFLD patients with no to minimal fibrosis at baseline (n=421), and validated in an independent NAFLD cohort (n=78). The FPS was used to assess response to 13 candidate anti-fibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n=78), and cenicriviroc in NASH patients enrolled in a clinical trial (n=19, NCT02217475). A serum-protein-based surrogate FPS (FPSec) was developed and technically evaluated in a liver disease patient cohort (n=79). Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (aOR=10.93, AUROC=0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacological target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate anti-fibrotics identified rational combination therapies based on epigallocatechin gallate, some of which were validated for enhanced anti-fibrotic effect in ex vivo culture of clinical liver tissues. In NASH patients treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of PPARalpha pathway was absent in patients without fibrosis improvement, suggesting benefit of combining PPARalpha agonism to improve anti-fibrotic efficacy of cenicriviroc. A 7-protein FPSec panel showed concordant prognostic prediction with FPS. Conclusion: FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform anti-fibrotic drug development.
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Project description:Non-alcoholic steatohepatitis (NASH) represents a major economic burden and is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat this condition. Emerging data suggests an important role of autophagy in this condition, which serves to degrade intracellular lipid stores, reduce hepatocellular damage, and dampen inflammation. Autophagy is primarily regulated by the transcription factors TFEB and TFE3, which are negatively regulated by mTORC1. Given that FLCN is a mTORC1 activator, we generated a liver-specific Flcn knockout mouse model to study its role in NASH progression. We demonstrate that loss of FLCN results in reduced triglyceride accumulation, fibrosis, and inflammation in mice exposed to a NASH-inducing diet. Furthermore, this study identifies a potential mechanism for NASH protection through autophagy activation resulting from the loss of FLCN. These results show an unexpected role for FLCN in NASH progression and highlight new possibilities for treatment strategies through its role in hepatocyte homeostasis.
2020-08-27 | GSE156918 | GEO