FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model
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PROVIDER: PRJNA659508 | ENA |
REPOSITORIES: ENA
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Project description: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.
2020-08-27 | GSE156918 | GEO
Project description:We applied RNA sequencing (RNA-seq) to study the gene expression profile in the liver of GAN DIO-NASH-HCC mice (non-tumorous tissue samples, n=9; tumor samples, n=9) and chow-fed controls (healthy liver samples, n=5)). Comparing tumour tissue of GAN DIO-NASH-HCC mice to healthy chow-fed controls, we find that tumors of GAN DIO-NASH-HCC mice show widespread regulations of genes associated with human HCC. Human HCC can be classified into three categories (S1-S3). Using the human S1-S3 gene classification described by Hoshida Y. et al. (2009), we find that GAN DIO-NASH-HCC tumors resemble the human S1 class of proliferating HCC tumors with poor prognosis.
2024-01-02 | GSE243976 | GEO
Project description:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
2023-08-09 | GSE240409 | GEO
Project description:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
2023-08-09 | GSE240406 | GEO
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
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress
Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.
2023-10-02 | GSE199637 | GEO
Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.
2023-10-02 | GSE199639 | GEO
Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.
2023-10-02 | GSE199638 | GEO
Project description:OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current study are to delineate the transcriptomic and proteomic signatures of NASH liver, to identify potential pathogenic pathways and factors, and to critically assess their role in NASH pathogenesis. METHODS: We performed RNA sequencing and quantitative proteomic analyses on the livers from healthy and diet-induced NASH mice. We examined the association between plasma levels of TSK, a newly discovered hepatokine, and NASH pathologies and reversal in response to dietary switch in mice. Using TSK knockout mouse model, we determined how TSK deficiency modulates key aspects of NASH pathogenesis. RESULTS: RNA sequencing and quantitative proteomic analyses revealed that diet-induced NASH triggers concordant reprogramming of the liver transcriptome and proteome in mice. NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK, whereas dietary switch reverses NASH pathologies and reduces circulating TSK concentrations. Finally, TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling. CONCLUSIONS: Global transcriptomic and proteomic profiling of healthy and NASH livers revealed the molecular signatures of diet-induced NASH and dysregulation of the liver secretome. Our study illustrates a novel pathogenic mechanism through which elevated TSK in circulation promotes NASH pathologies, thereby revealing a potential target for therapeutic intervention.
2019-01-08 | GSE119340 | GEO