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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

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

PROVIDER: PRJNA807693 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18053800.fastq.gz	Fastqsanger.gz
	SRR18053801.fastq.gz	Fastqsanger.gz
	SRR18053802.fastq.gz	Fastqsanger.gz
	SRR18053803.fastq.gz	Fastqsanger.gz
	SRR18053804.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

Therapeutic Efficacy, Biomarker Signatures and Translatability of Semaglutide in the Liver Biopsy-Confirmed GAN DIO-MASH Mouse Model (study 6)

Project description:12-week semaglutide treatment was characterized in the GAN-DIO MASH mice. Endpoints included body weight, plasma biochemistry and proteomics as well as liver histological and transcriptome assessments.

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Therapeutic Efficacy, Biomarker Signatures and Translatability of Semaglutide in the Liver Biopsy-Confirmed GAN DIO-MASH Mouse Model (study 7/9)

Project description:To investigate the effect of treatment duration on therapeutic efficacy, semaglutide was administered in the GAN-DIO MASH mice. Endpoints included body weight, plasma biochemistry as well as liver histological and transcriptome assessments.

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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

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.

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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.

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