Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model

ABSTRACT: Non-alcoholic steatohepatitis (NASH) represents a major economic burden and is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat this condition. Emerging data suggests an important role of autophagy in this condition, which serves to degrade intracellular lipid stores, reduce hepatocellular damage, and dampen inflammation. Autophagy is primarily regulated by the transcription factors TFEB and TFE3, which are negatively regulated by mTORC1. Given that FLCN is a mTORC1 activator, we generated a liver-specific Flcn knockout mouse model to study its role in NASH progression. We demonstrate that loss of FLCN results in reduced triglyceride accumulation, fibrosis, and inflammation in mice exposed to a NASH-inducing diet. Furthermore, this study identifies a potential mechanism for NASH protection through autophagy activation resulting from the loss of FLCN. These results show an unexpected role for FLCN in NASH progression and highlight new possibilities for treatment strategies through its role in hepatocyte homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE156918 | GEO | 2020/08/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model

Project description:FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model

| PRJNA659508 | ENA

An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation downstream of TSC2 loss

Project description:The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.

2022-11-01 | GSE216545 | GEO

Loss of the Tumor Suppressor FLCN Promotes Breast Tumor Growth by Inducing a TFE3-Dependent Program Driving Warburg Effect and Angiogenesis

Project description:Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The FLCN tumor suppressor complex (FLCN, FNIP1, FNIP2) has been implicated in the regulation of energy homeostasis via two metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here we reveal that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers including poor prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared to the luminal, less aggressive subtypes. We show that FLCN loss in luminal subtypes promotes tumor growth through TFE3 activation and subsequent induction of several pathways including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN deficient cells was dictated by the activation of PGC-1⍺/HIF-1⍺ pathway, which we show to be TFE3-dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Thus, FLCN loss induces TFE3-dependent breast tumor growth through activation of multiple mechanisms, including previously unreported roles in aerobic glycolysis and angiogenesis. These findings could point to a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.

2020-12-23 | GSE163791 | GEO

Loss of FLCN-FNIP1/2 Induces a Non-Canonical Interferon 1 Response in Human Renal Tubular Epithelial Cells

Project description:Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene that has been linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown Here we show that FLCN loss activates E-box target genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD, yet without modifying mTORC1 activity. Surprisingly, inactivation of FLCN or its binding partners FNIP1/FNIP2 activates interferon response genes but independently of interferon. Mechanistically, FLCN loss promotes recruitment of STAT2 to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint novel prognostic biomarkers.

2021-02-11 | PXD021346 | Pride

Gene expression data from FLCN-restored UOK257-2 renal cancer cells

Project description:UOK257 cell line was derived from a BHD patient. It harbors a germline mutation in FLCN (c.1285dupC) and LOH. UOK257-2 cells were generated from UOK257 cells by introducing wildtype FLCN using retrovirus. FLCN inactivation induces TFE3 transcriptional activity by increasing its nuclear localization. Thus expression microarray was used to identify the genes regulated by FLCN and TFE3. UOK257-2 cells expressing wildtype FLCN were transfected with 1) scrambled, 2) FLCN, 3) TFE3 and 4)FLCN/TFE3 siRNAs with Lipofectamine 2000 transfection reagent. Cells were harvested 3 days after transfection and RNAs were isolated using Trizol reagent and RNeasy Mini Kit. The genes induced by FLCN siRNA and reduced by TFE3 siRNA were chosen as a candidate genes regulated by FLCN and TFE3.

2010-10-11 | E-GEOD-23614 | biostudies-arrayexpress

Identification of differentially regulated genes in flcn-1 mutant C. elegans

Project description:Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disorder that is characterized by the clinical triad of benign skin tumors - so-called fibrofolliculomas, recurrent pneumothoraces due to pulmonary cysts and the formation of kidney tumors. The molecular function of Folliculin (FLCN), the protein product of the BHD gene mutated in this syndrome, has remained elusive to a large extent. Animal models such as mouse, rat and canine models have been used to elucidate parts of the pathway in which FLCN plays a role showing it to interfere with AMP-kinase and mTOR signaling. Caenorhabditis elegans provides - due to its simple genetic amenability and large brood size - the perfect tool to study signal transduction pathways in detail. Thus, we decided to examine F22D3.2 (flcn-1) - a putative orthologue of FLCN in the nematode. We established the first gene expression profiles of a strain harboring a mutation in flcn-1 compared to WTN2 allowing for a first insight into the function of this gene in C. elegans. This study examines the transcriptome of the flcn-1 mutant strain RB1035 in comparison to WTN2 in order to identify differentially regulated genes. RNA was prepared from pre-reproductive adults in both WTN2 and RB1035 (harboring a flcn-1 mutant allele, mutant worms had been backcrossed wo WTN2 8 times) using biological triplicates. RNA was labeled and hybridized to Agilent C. elegans whole genome microarrays and scanned using a Agilent Technologies Scanner G2505C US22502540.

2012-12-31 | E-GEOD-43207 | biostudies-arrayexpress

A defect in endothelial autophagy occurs in patients with nonalcoholic steatohepatitis and promotes inflammation and fibrosis

Project description:Autophagy is a physiological process controlling endothelial homeostasis in vascular beds outside the liver. This study demonstrates that autophagy is defective in liver endothelial cells of patients with NASH and that this defect promotes liver inflammation and fibrosis at early stages of NASH, but also at advanced stages of chronic liver disease. We used transcriptomic analysis to evaluate the global effect of autophagy deficiency in liver sinusoidal endothelial cells' (LSECs) gene expression

2022-10-14 | GSE138875 | GEO

Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model

Project description:BCAA were administered to atherogenic and high-fat (Ath & HF) diet-induced nonalcoholic steatohepatitis (NASH) model mice and platelet-derived growth factor C transgenic mice (Pdgf-c Tg). Liver histology, tumor incidence, and gene expression profiles were evaluated. BCAA supplementation improved hepatic steatosis, inflammation, fibrosis, and tumors in the NASH mouse model, possibly through the modification of mTORC1 signaling.

2017-06-12 | GSE57290 | GEO

An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis

Project description:Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplantation, with no approved therapeutics available. Despite years of research, the exact molecular mechanism of NASH progression is not well understood, but fat accumulation is believed to be the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long term gene silencing with single subcutaneous administration. Here we identified a hyper-functional, fully chemically stabilized Gal-Nac conjugated siRNA targeting DGAT2 (Dgat2-1473) that upon injection elicits up to three months of DGAT2 silencing (>80-90%, p<0.0001) in wild-type and NSG-PiZ “humanized” mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (> 50%, p:0.0008), resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat didn’t translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.

2022-12-31 | GSE178987 | GEO

Identification of differentially regulated genes in flcn-1 mutant C. elegans

2012-12-31 | GSE43207 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data