Similar Datasets
Project description:We generated hepatocyte-specific profiles of the transcriptional landscapes during NASH progression using the INTACT methodology.
2021-07-01 | GSE162876 | GEO
Project description:Cell Type-Resolved Genomic Profiling of NASH and liver fibrosis
| PRJNA683621 | ENA
Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
2021-07-13 | PXD025691 | Pride
Project description:Hepatocyte-specific Genomic and Transcriptional Profiling of NASH and liver fibrosis
| PRJNA683627 | ENA
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 a potential application of 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 onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver 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-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, 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.
2018-11-27 | GSE114261 | GEO
Project description:Hepatocellular carcinoma (HCC), the third most common cancer, originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged primarily by viruses or nonalcoholic steatohepatitis (NASH)1,2. While increasing HCC risk3, NASH also induces TP53-dependent hepatocyte senescence4. How this tumor-suppressive response is activated but eventually bypassed to license HCC progression is unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target, induced in senescent NASH hepatocytes but downregulated in most human HCCs. Initial FBP1 downregulation in disease-associated hepatocytes, whose accumulation precedes HCC development5, activates AKT to inhibits GSK3 substrate binding, thereby augmenting activation of NRF2 which accelerates FBP1 and TP53 degradation. Intrinsic NRF2 activation and FBP1 loss trigger overlapping transcriptomic responses that suppress senescence, enhance hepatocyte proliferation and metabolism, and enable NRAS- or NASH-induced hepatocarcinogenesis. This AKT-dependent metabolic switch, operative in mice and humans, controls NASH to HCC progression. Our results further suggest that NASH-related hepatocyte senescence is triggered by hypernutrition-induced single strand DNA breaks. Senescence reversal enables HCC progenitor expansion and somatic mutagenesis.
2024-07-15 | GSE240047 | GEO
Project description:We generated profiles of fasting-induced changes in the genomic landscapes of in vivo hepatocytes using the INTACT methodology.
2021-08-30 | GSE181937 | GEO
Project description:Necroptosis contributes to hepatocyte death (HC) in non-alcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs is associated with worsening NASH in humans and in mice with diet-induced NASH and that NASH liver showed evidence of impaired necHC clearance by liver macrophages. Further, the "don't-eat-me" ligand CD47 on HCs and its receptor, SIRPα, on liver macrophages, were markedly upregulated in human and mouse NASH. In vitro, anti-CD47 or anti-SIRPα promoted necHC engulfment by primary liver macrophages. In a proof-of-concept mouse model of inducible HC necroptosis, anti-CD47 increased necHC uptake by liver macrophages and inhibited hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Most importantly, treatment of two mouse models of diet-induced NASH with anti-CD47 or anti-SIRPα increased the uptake of necHC by liver macrophages and decreased HSC activation and liver fibrosis. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα upregulation contributes to fibrotic NASH and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.
2022-11-25 | GSE197111 | GEO
Project description:Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress-induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive. Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA-seq and ChIP-seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte-specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated the molecular signature of NASH and sensitized mice to diet-induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB that promotes inflammatory signaling in hepatocytes and stress-induced cell death. These findings illustrate a novel mechanism through which disruptions of chromatin architecture drive the emergence of disease-specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis.
2019-09-10 | GSE131336 | GEO
Project description:To understand the fibrotic response in the CDA-HFD induced NASH fibrosis model, we performed RNA-seq on liver samples collected from mice fed with normal chow (week 0) or CDA-HFD chow (weeks 8 and 16).
2022-08-19 | GSE207856 | GEO