Metabolic skewing in inflammatory hepatic Th17 cells regulates non-alcoholic fatty liver disease (NAFLD) pathogenesis
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ABSTRACT:
PROVIDER: PRJNA577097 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10267100_1.fastq.gz | Fastqsanger.gz | |||
| SRR10267100_2.fastq.gz | Fastqsanger.gz | |||
| SRR10267200_1.fastq.gz | Fastqsanger.gz | |||
| SRR10267200_2.fastq.gz | Fastqsanger.gz | |||
| SRR10267101_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To determine the Th17 milleu in the liver during NAFLD in the context of Diet induce obesity Methods: Mice were place on a highfat diet for 20 weeks, Th17 cells were isolated from the liver by FACS sorting the TCRb+CD4+IL-17A-GFP+ cells. Single cells were separated into 6 C1 capture chips and RNA sequencing was performed at an average depth of 3 million paired-end reads (75nt) using the Illumina HiSeq 2500, with SMART-Seq2 version 2 chemistry as recommended by the manufacturer. Results: Here, we demonstrate that NAFLD progression is associated with polarization and accumulation of a unique population of inflammatory hepatic CXCR3+Th17 cells (ihTh17) in mice. Transfer of ihTh17 cells accelerated and exacerbated NAFLD pathogenesis in vivo. Notably, ihTh17 cells, compared to conventional CXCR3-Th17 cells, exhibited increased open chromatin marks in enhancer regions, increased metabolic capacity, and were able to simultaneously produce an array of proinflammatory cytokines which directly contributed to hepatocellular damage. Modulation of the CXCR3-CXCL9/10 axis and ihTh17 metabolic state was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Conclusions: In sum, our data show that the obesity-associated environment regulates Th17 cell competence towards an ihTh17 fate and that the preferential use of glycolytic pathways in ihTh17 cells promotes their inflammatory vigor and contributes to NAFLD progression.
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2018-03-15 | E-MTAB-4856 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
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2014-11-07 | E-GEOD-63067 | biostudies-arrayexpress
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2019-10-17 | GSE138946 | GEO
Project description:Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis1-7. Based on hepatic expression quantitative trait loci analysis it has been suggested that MBOAT7 loss of function promotes liver disease progression1-7, but this has never been formally tested. Here we show that Mboat7 loss, but not Tmc4, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. Mboat7 loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of N
2019-10-17 | GSE138945 | GEO
Project description:Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.
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