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INTEAM CONSORTIUM - ALCOHOLIC HEPATITIS LIVER RNA SEQUENCING

ABSTRACT: INTEAM CONSORTIUM - ALCOHOLIC HEPATITIS LIVER RNA SEQUENCING

PROVIDER: PRJNA531222 | ENA |

REPOSITORIES: ENA

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INTEAM CONSORTIUM - ALCOHOLIC HEPATITIS LIVER RNA SEQUENCING

Project description:INTEAM CONSORTIUM - ALCOHOLIC HEPATITIS LIVER RNA SEQUENCING

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InTEAM Consortium - Alcoholic Hepatitis

Project description:Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we describe the transcriptional programs involved in disease progression. We uncovered that development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). The PPARG predicted activation state was found increased in early forms of ALD, while AH was associated by a marked decrease in HNF4A-dependent gene expression along with a marked expression of the fetal HNF4A isoform (P2). TGFB1, a key upstream transcriptome regulator in AH, induced the use of HNF4a P2 promoter in hepatocytes, which resulted in abnormal bile acid synthesis and defective metabolic and synthetic functions. PPARG agonists partially prevented this effect. We conclude that targeting TGFB1 and epigenetic drivers that modulate HNF4A-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. The study was conducted thanks to a multicenter collaboration under the National Institute of Alcohol Abuse and Alcoholism (NIAAA)-funded consortium: Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTEAM).

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Super Enhancer Regulation of Cytokine-Induced Chemokine Production in Alcoholic Hepatitis [RNA-Seq]

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Project description:Intrahepatic lipocalin 2 promotes liver fibrosis in alcoholic hepatitis

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Intrahepatic lipocalin 2 promotes liver fibrosis in alcoholic hepatitis [RNA-Seq]

Project description:Our project is to explore the molecular subtypes for targeted therapies in Alcoholic Hepatitis (AH). We have found that LCN2 gene expression is markedly induced in AH patients and correlated to the disease severity including portal hypertension. Animal data from microarray experiments show that compared with the wild mice, LCN2 knockout mice are protected from CCl4-induced liver fibrosis. The focus of our current study is to investigate the effect of overexpression of LCN2 on functional changes in hepatocytes. To this end, HepG2 cells and human primary hepatocytes (HPH) were overexpressed human LCN2 gene and samples were analyzed through RNA-sequencing.

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Multicellular liver organoid model for recapitulating hepatitis C virus infection and non-alcoholic fatty liver disease progression [RNA-Seq]

Project description:Hepatitis C virus (HCV) infection has been successfully managed by anti-viral therapies, however, high prevalence to severe chronic liver disease state including non-alcoholic fatty liver disease (NAFLD) is a problem encountered even after the cure of hepatitis C. Moreover, there is currently no reliable in vitro model capable of investigating host-viral interactions and monitoring the progression of viral hepatitis to chronic liver diseases. Recent organoid technology has been reported for successful infection of HCV, but there is still lack of non-parenchymal cells, which play a crucial role in disease progression. Here, we provided a novel multicellular liver organoid model using co-culture system of macrophages and liver organoids differentiated from the same cell source, human embryonic stem cells. Surprisingly, HCV infection led potent lipid accumulation in liver organoids through regulation of host lipid metabolism, which was further promoted by macrophage co-culture. Lipid enriched condition provided by longterm-treatment with fatty acid accelerated potent HCV amplification and further promotion of inflammation and fibrosis progression. Therefore, our model may be a valuable novel platform recapitulating diverse phenotypes with host-virus intercommunication and inter-cellular interactions and further progressive features of hepatitis C-associated chronic NAFLD progression of patients with HCV.

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Intrahepatic lipocalin 2 promotes liver fibrosis in alcoholic hepatitis [RNA-Seq]

Project description:Intrahepatic lipocalin 2 promotes liver fibrosis in alcoholic hepatitis [RNA-Seq]

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Intrahepatic lipocalin 2 promotes liver fibrosis in alcoholic hepatitis [array]

Project description:Intrahepatic lipocalin 2 promotes liver fibrosis in alcoholic hepatitis [array]

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Super Enhancer Regulation of Cytokine-Induced Chemokine Production in Alcoholic Hepatitis [ChIP-Seq 2]

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