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Prognostic Liver Signature for NAFLD (PLS-NAFLD) profiles of cell-based PLS system treated with free fatty acids (FFA) and IDO1 inhibitor, epacadostat.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD), alongside the global obesity epidemic, is rapidly emerging as a dominant liver disease etiology that leads to progressive liver fibrosis, its terminal stage, cirrhosis, and hepatocellular carcinoma (HCC). We identified and validated a 133-gene signature (Prognostic Liver Signature for NAFLD [PLS-NAFLD]) to predict long-term HCC risk in patients with NAFLD. By analyzing PLS-NAFLD, IDO1 was identified as a potenial chemopreventive target for HCC from NAFLD. To test this hypothesis, we utilized our clinical-prognostic-signature-inducible cell culture model. We first confirmed that free fatty acid treatment (800 μM oleic acid and 400 μM palmitic acid) can induce PLS-NAFLD, then IDO1 inhibitor, epacadostat, can reverse the high-risk pattern in a dose-dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200460 | GEO | 2022/07/01

REPOSITORIES: GEO

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Prognostic Liver Signature for NAFLD (PLS-NAFLD) profiles of cell-based PLS system treated with free fatty acids (FFA) and IDO1 inhibitor, epacadostat.

Project description:Prognostic Liver Signature for NAFLD (PLS-NAFLD) profiles of cell-based PLS system treated with free fatty acids (FFA) and IDO1 inhibitor, epacadostat.

| PRJNA824585 | ENA

A human liver cell-based system modeling a clinical prognostic liver signature combined with single-cell RNA-Seq for discovery of liver disease therapeutics

Project description:Abstract: Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. We developed a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in NASH-HCC animal models and patient-derived tumorspheroids, we identified nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Perturbation studies combined with scRNA-Seq analyses of patient liver tissues uncovered HRH2+, CLEC5Ahigh, MARCOlow liver macrophages and hepatocytes as nizatidine targets. The PLS model combined with scRNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

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A human liver cell-based system modeling a clinical prognostic liver signature combined with single-cell RNA-Seq for discovery of liver disease therapeutics

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Transcriptome profile of liver biopsy tissues from patients with non-alcoholic fatty liver disease (tissue validation set 2).

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

Transcriptome profile of liver biopsy tissues from patients with non-alcoholic fatty liver disease (tissue validation set 1).

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Transcriptome profile of liver biopsy tissues from patients with non-alcoholic fatty liver disease (derivation set).

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RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [m6A-seq]

Project description:Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy on NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation while Mettl3 knockout exerted an opposite effect in mice. Single-cell RNA-seq revealed that METTL3 suppressed antitumor immune response by reducing infiltration of Gzmb+ and IFN-γ+ CD8+ T-cell, thereby facilitating immune escape. Mechanistically, METTL3 mediates SCAP mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters, lipotoxins that impaired CD8+ T cell function in tumor microenvironment. Targeting of METTL3 by sgRNA, nanoparticle-siRNA, or pharmacological inhibitor (STM2457) in combination with anti-PD1 synergized to reinvigorate cytotoxic CD8+ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

2023-08-23 | GSE233807 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [RNA-Seq]

2023-08-23 | GSE233806 | GEO

Prognostic Liver Signature profiles in biopsy tissues from non-alcoholic fatty liver disease (NAFLD) patients in Japan

Project description:Prognostic Liver Signature profiles in biopsy tissues from non-alcoholic fatty liver disease (NAFLD) patients in Japan

| PRJNA679603 | ENA

Tid1 Deficiency Disrupting Mitochondria to Drive NASH-Dependent Hepatocellular Carcinoma Progression

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

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