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Cell Type-Resolved Genomic Profiling of NASH and liver fibrosis

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

PROVIDER: PRJNA683621 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13219975_1.fastq.gz	Fastqsanger.gz
	SRR13219975_2.fastq.gz	Fastqsanger.gz
	SRR13219976_1.fastq.gz	Fastqsanger.gz
	SRR13219976_2.fastq.gz	Fastqsanger.gz
	SRR13219977_1.fastq.gz	Fastqsanger.gz

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Cell Type-Resolved Transcriptional Profiling of NASH and liver fibrosis

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

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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 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.

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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.

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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.

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