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Hepatocyte-specific Genomic and Transcriptional Profiling of NASH and liver fibrosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE162878 | GEO | 2021/07/01

REPOSITORIES: GEO

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Hepatocyte-specific Genomic and Transcriptional Profiling of NASH and liver fibrosis

Project description:Hepatocyte-specific Genomic and Transcriptional Profiling of NASH and liver fibrosis

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Cell Type-Resolved Genomic Profiling of NASH and liver fibrosis

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Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis.

Project description:Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)-induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)-modified siRNA, both of which reduced NASH diet-induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.

| S-EPMC8792974 | biostudies-literature

Cell Type-Resolved Transcriptional Profiling of NASH and liver fibrosis

Project description:We generated hepatocyte-specific profiles of the transcriptional landscapes during NASH progression using the INTACT methodology.

2021-07-01 | GSE162876 | GEO

BET Inhibition Improves NASH and Liver Fibrosis.

Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-? expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.

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Cell Type-Resolved Genomic Profiling of NASH and liver fibrosis

Project description:Cell Type-Resolved Genomic Profiling of NASH and liver fibrosis

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Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver.

Project description:Background & aimsNonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH.MethodsHepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet.ResultsHFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH.ConclusionsBecause of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.

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Hepatocyte CCAAT/enhancer-binding protein alpha restricts liver fibrosis by inhibiting secreted phosphoprotein 1 expression

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-08 | GSE214616 | GEO

Transcriptional Profiling of NASH mice with hepatocyte-specific knock down of Elf3 or Glis2

Project description:We performed RNA-seq of livers obtained from mice fed either a control or the NASH-inducing FPC diet (Wang et al., 2016) for 24wk. In some FPC-fed mice the NASH-activated transcription factors, Elf3 or Glis2, had been deleted specifically in hepatocytes, when mice reached a steatotic state.

2021-07-01 | GSE162869 | GEO

Cell Type-Resolved Transcriptional Profiling of NASH and liver fibrosis

Project description:Cell Type-Resolved Transcriptional Profiling of NASH and liver fibrosis

| PRJNA683628 | ENA