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Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis

ABSTRACT: Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis

PROVIDER: PRJNA1020832 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26170015.fastq.gz	Fastqsanger.gz
	SRR26170016.fastq.gz	Fastqsanger.gz
	SRR26170017.fastq.gz	Fastqsanger.gz
	SRR26170018.fastq.gz	Fastqsanger.gz
	SRR26170019.fastq.gz	Fastqsanger.gz

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Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

Project description:Non-alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence-based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO-NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose and cholesterol for 28-88 weeks. GAN DIO-NASH mice with biopsy-confirmed NASH and fibrosis received low-caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within-subject change in NAFLD Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning-based image analysis. GAN DIO-NASH mice showed clear and reproducible progression in NASH, fibrosis stage and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, while only lanifibranor induced regression in fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of dietary intervention, semaglutide and lanifibranor was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO-NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO-NASH mice in preclinical drug development.

2022-02-21 | GSE196908 | GEO

Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis

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

Dietary intervention reverses molecular signatures of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

Project description:We applied RNA sequencing (RNA-seq) to study the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse model of NASH. GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16, or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. We find that chow reversal promoted substantial benefits on metabolic, biochemical and histological outcomes accompanied by marked suppression of gene expression markers of hepatocellular senescence in GAN DIO-NASH mice. These therapeutic benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.

2024-01-16 | GSE246328 | GEO

Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

Project description:Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

| PRJNA807693 | ENA

Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis.

Project description:Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12-72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.

| S-EPMC10754821 | biostudies-literature

Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

Project description:Non-alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence-based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO-NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28-88 weeks. GAN DIO-NASH mice with biopsy-confirmed NASH and fibrosis received low-caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within-subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning-based image analysis. GAN DIO-NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO-NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO-NASH mice in preclinical drug development.

| S-EPMC9099137 | biostudies-literature

Dietary intervention reverses molecular signatures of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

Project description:Dietary intervention reverses molecular signatures of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

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Expression data of mouse gastric tumors (TNF KO-Gan and BALB/c-Gan mice )

Project description:Gan mice express Wnt1, Ptgs2, and Ptges, which develop inflammation-associated gastric tumors (Oshima et al, Gastroenterology 131: 1086, 2006). We examined the role of TNF-alpha in tumorigenesis by construction of TNF-/- Gan mice. We also examined genetic background difference in tumor phenotype by changing Gan mouse background from C57BL/6(B6) to BALB/c. Microarray analyses were performed to examine changes of expression profiles in tumors by TNF gene disruption or by changing genetic background. Total RNA was prepared from B6 Gan mice (n=3: Gan1-Gan3), B6-Gan TNF-/- mice (n=3: Gan(TNF KO)1-Gan(TNF KO)3), BALB-Gan mice (n=3: Gan(BALB/c)1-Gan(BALB/c)3), and wid-type normal glandular stomach (n=3: WT1-WT3). We used Affymetrix microarrays for hybridization, and examined expression profiles.

2012-12-27 | E-GEOD-43145 | biostudies-arrayexpress

Gene expression analysis of three tumor organoids (GAN-WT, GAN-p53 and GAN-KP) derived from gastric tumor in K19-Wnt1/C2mE (GAN) mouse.

Project description:To develop a syngeneic mouse model of metastatic gastric cancer, we established the tumor organoids from gastric tumor arising in GAstric Neoplasia (GAN) mice (GAN-WT) which express Wnt1 and the PGE2 synthesis enzymes COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach epithelium. Furthemore, GAN-WT organoids were genetically manupilated into p53 knockout organoids (GAN-p53KO) and KrasG12V-expressing GAN-p53KO organoids (GAN-KP).

2021-06-15 | GSE178087 | GEO

Expression data of mouse gastric tumors (TNF KO-Gan and BALB/c-Gan mice )

2012-12-27 | GSE43145 | GEO