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A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [Cut&Tag]

ABSTRACT: A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [Cut&Tag]

PROVIDER: PRJNA842774 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19424310_1.fastq.gz	Fastqsanger.gz
	SRR19424310_2.fastq.gz	Fastqsanger.gz
	SRR19424311_1.fastq.gz	Fastqsanger.gz
	SRR19424311_2.fastq.gz	Fastqsanger.gz
	SRR19424312_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [Cut&Tag]

Project description:The breakdown of toll-like receptor (TLR) tolerance results in tissue damage. Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a crucial negative regulator of TLR signaling. MBOAT7 deficiency in macrophages as observed in patients with metabolic (dysfunction) associated fatty liver disease (MAFLD) and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can be exploited as a therapeutic target for diseases associated with dysregulation of the TLR signaling cascade.

2022-10-21 | GSE204964 | GEO

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [ATAC-seq]

2022-10-21 | GSE204963 | GEO

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [RNA-seq]

2022-10-21 | GSE204962 | GEO

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.

Project description:A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.

| PRJNA842773 | ENA

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [ATAC-seq]

Project description:A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [ATAC-seq]

| PRJNA842775 | ENA

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [RNA-seq]

Project description:A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [RNA-seq]

| PRJNA842776 | ENA

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.

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

2022-10-21 | GSE204965 | GEO

MBOAT7's role in the progression of Non-alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)

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

Loss of hepatic Mboat7 leads to liver fibrosis

Project description:Objective: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. Design: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7 Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. Results: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7 Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7 Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol (LPI) levels. The altered LPI and phosphatidylinositol subspecies in MBOAT7 Δhep livers and humans rs641738TT carriers were similar. Conclusion: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

2020-06-30 | GSE139992 | GEO

MBOAT7-Driven Lysophosphatidylinositol Acylation in Adipocytes Contributes to Systemic Glucose Homeostasis

Project description:We previously demonstrated that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7, the gene encoding Membrane Bound O-Acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated floxed Mboat7 mice and created hepatocyte- and adipocyte-specific knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. After chow and high fat diet feeding (60% kCal fat), mice were subjected to metabolic phenotyping and tissues to molecular workup and analysis. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ~100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

2023-05-10 | PXD039894 | Pride

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