Prognostic Liver Signature profiles in biopsy tissues from non-alcoholic fatty liver disease (NAFLD) patients in Japan
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PROVIDER: PRJNA679603 | ENA |
REPOSITORIES: ENA
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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.
2021-12-22 | GSE161841 | GEO
Project description:Prognostic Liver Signature profiles in biopsy tissues from non-alcoholic fatty liver disease (NAFLD) patients in the U.S.
| PRJNA633480 | ENA
Project description:FLORINASH - The role of intestinal microflora in non-alcoholic fatty liver disease (NAFLD) EU FP7-HEALTH, project number 241913<br>Florinash examined the role on the gut microbiota in NAFLD. Metagenomic, proteomic, metabolomic and transcriptomic data were integrated to give provide a systems biology approach to disease-associated studies. Liver biopsies were obtained from patients undergoing bariatric surgery; one was used to diagnose NAFLD, the other was used to examine the host transcriptome in NAFLD. This dataset is part of the TransQST collection.
2018-03-15 | E-MTAB-4856 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
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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 fatty liver disease (NAFLD) is of increasing prevalence and concern. NAFLD can progress to non-alcoholic steatohepatitis (NASH), to cirrhosis and finally to end-stage liver disease where liver transplantation is required. We aimed to characterise this progression by performing single nuclei transcriptomic analysis of liver biopsies taken from patients across the disease spectrum. We have observed that hepatocytes are the cell type affected mostly by the disease and describe plasticity between cell types which may represent a regenerative process.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is a major global health problem with its high prevalence and risk of developing lethal complications, progressive liver fibrosis and hepatocellular carcinoma (HCC), the only rising cancer mortality in the U.S. For early HCC detection to improve the dismal prognosis, there is an urgent unmet need to identify a subset of NAFLD patients with elevated risk of HCC. Herein, we derived a hepatic-transcriptome-based NAFLD-specific HCC risk biomarker, PLS-NAFLD, and validated it in two independent cohorts of HCC-naive and experienced NAFLD patients..
2022-07-01 | GSE193080 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a major global health problem with its high prevalence and risk of developing lethal complications, progressive liver fibrosis and hepatocellular carcinoma (HCC), the only rising cancer mortality in the U.S. For early HCC detection to improve the dismal prognosis, there is an urgent unmet need to identify a subset of NAFLD patients with elevated risk of HCC. Herein, we derived a hepatic-transcriptome-based NAFLD-specific HCC risk biomarker, PLS-NAFLD, and validated it in two independent cohorts of HCC-naive and experienced NAFLD patients.
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