Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [NASH Custom panel]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE240409 | GEO | 2023/08/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [Fibrosis panel]

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

Post-transplant (non-alcoholic steatohepatitis) NASH compared with transplanted normal controls

Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.

2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress

The synergestic effects of western diet and carbon tetrachloride (CCl4) to develop non-alcoholic steatohepatitis (NASH) and liver tumor in mice

Project description:NASH is a combination of hepatic steatosis and severe inflammation, which can lead to fatal liver disease such as cirrhosis and hepatocellular carcinoma. While a variety of models have been descirbed, they have several limitations. Therefore, it is of urgent importance to create animal model that recapitulate the physiology, histology and outcome seen in human with NASH. We created western diet-fed and CCl4-treated mouse model. they showed characteristic histological features of NASH such as fibrosis, ballooning and steatosis at 12 weeks and liver cancers developed at 24 weeks. Their transcritomic changes were also similar to those seen in human NASH.

2018-03-28 | GSE99010 | GEO

Hepatic ACLY deficiency and bempedoic acid drive divergent responses to dietary lipid

Project description:ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in non-alcoholic fatty liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which has been shown to improve steatosis in mice. However, the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to support DNL, potentially complicating the targeting of ACLY. We show that hepatic loss of both ACLY and ACSS2 reduces DNL. Nevertheless, even when ACSS2 is suppressed by dietary or genetic means, we find that steatosis is counterintuitively exacerbated with hepatic ACLY deficiency in mice fed a Western diet (WD), linked to reduced expression of PPARa target genes controlling fatty acid oxidation. Conversely, BPA treatment increased fat catabolism and ameliorated WD-mediated lipid accumulation in both WT and liver ACLY knockout mice. Thus, hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and BPA improves steatosis independent of ACLY.

2024-08-01 | GSE247358 | GEO

NASH

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

Hepatic transcriptomic changes during non-alcoholic steatohepatitis (NASH)-associated liver carcinogenesis in mice

Project description:Hepatocellular carcinoma (HCC), which accounts for 90% of all primary livers tumors, is the fourth most common cancer in the world. The development of HCC is a long-term and complex process, and uncovering the molecular mechanisms associated with HCC development is critical for the disease diagnosis, prevention, and treatment. Exploring these mechanisms using human HCC samples is desirable, but frequently impractical, with a number of limitations and shortcomings. The STAMTM (Stelic Institute & Co, Tokyo, Japan) mouse model of NASH-associated liver carcinogenesis is considered a useful and relevant model for investigating the molecular pathogenesis of NASH-derived HCC. This model resembles the human HCC development associated with progression from simple steatosis to NASH, fibrosis, and HCC. In the present study, by using high-throughput whole genome microarrays (SurePrint G3 Mouse Gene Expression v2, 8x60K; Agilent Technologies, Santa Clara, CA), we examined the transcriptomic profiles in the livers of STAMTM mice at different stages of liver carcinogenesis, including steatosis (6 week time interval), NASH (8 weeks), fibrotic stage (12 weeks), and in full-fledged HCC (20 weeks). The results of microarray analyses showed significant progressive changes in hepatic gene expression during the development of HCC. A total of 970, 1462, 2742, and 2857 of differentially expressed genes were identified in the livers at 6, 8, 12, and 20 weeks, respectively. Detailed analysis of these differentially expressed genes will benefit the understanding of the underlying mechanisms of non-alcoholic fatty liver disease-derived HCC. Transcriptomic profile in the liver of STAM mice at 6 weeks (steatosis; n=3), 8 weeks (steatohepatitis; n=3) 12 weeks (fibrosis; n=4) and 20 weeks (HCC-stage tumor tissue, n=4) weeks. Age-matched control samples were also analyzed.

2016-06-22 | E-GEOD-83596 | biostudies-arrayexpress

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [NASH Custom panel]

Project description:Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [NASH Custom panel]

| PRJNA1003527 | ENA

Expression data from NASH-induced mouse liver treated with isorhamnetin

Project description:Gene expression profiling reveals a potential role of isorhamnetin in the mitigation of NASH features including steatosis, liver injury, and fibrosis Microarray gene expression profiling was conducted for technical replicates of healthy liver as control (CTL), NASH-induced (NASH), NASH-induced treated with isorhamnetin for 14 days (50 mg/kg of body weight) (NASH+ISO) liver tissues to identify its effect in the regulation of pathways involved in pathologic features of NASH.

2019-09-19 | GSE137635 | GEO

The effects of CD4 T cell Nr4a family on NASH progression

Project description:NASH is characterized by hepatic steatosis, inflammation, fibrosis and liver damage, which eventually results in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying NASH progression remain largely unknown. In this study, we aimed to elucidate the impact of Nr4a family in CD4 T cells in NASH development.

2024-10-13 | GSE241515 | GEO

The effects of CD4 T cell Nr4a family on NASH progression (RNA-Seq)

2024-10-13 | GSE241657 | GEO